When the manuscript was first shown to expert cryptologists, they thought that solving it would be easy as the text was composed of "words", some of which were more frequent and occurred in certain combinations. This soon turned out to be a mistake; the text could not easily be converted into Latin, English, German or a host of other languages which might possible be at the base of this document.

A first "solution" was announced in 1919, by William Romaine Newbold, who caused a sensation by claiming that the manuscript did indeed contain the work of Roger Bacon and that Bacon had known the use of the compound telescope and microscope, seeing the spiral structure of the Andromeda galaxy only visible with modern telescopes and cell structures unknown in the 13th Century. This solution was finally disproved by Manly in 1931.

The attempts to crack the code, however, were not over. In 1931, Mrs. Voynich took a photostatic copy of the manuscript to Catholic University in Washington where Fr. Theodore Petersen reproduced it photographically and started a complete hand transcription of the manuscript, with a card index to the words, and lists of concordances. The transcription alone was reported to have taken him 4 years. Unfortunately, it is not known what conclusion, if any, he reached.

In 1944, Hugh O'Neill, a renowned botanist at the Catholic University, identified various plants depicted in the manuscript as New-World species, in particular an American sunflower and a red pepper. This meant that the dating of the manuscript should be placed after 1493, when Columbus brought the first sunflower seeds to Europe. However, the identification is not certain: the red pepper is coloured green and the sunflower identification is equally contested.

Other people involved in the study of the manuscript were prominent cryptologists such as W. Friedman and J. Tiltman, who independently arrived at the hypothesis that the manuscript was written in an artificial, constructed language. This was based on the structure of the "words" as described elsewhere. Such artificial languages were devised at least a century after the probable date of the Voynich manuscript. Only the 'Lingua Ignota' of Hildegarde of Bingen (1098-1179) predates the Voynich manuscript by several centuries, but this language does not exhibit the structure observed by Friedman and Tiltman, and it provides only nouns and a few adjectives.

Later acclaimed solutions see in the manuscript a simple substitution cipher which can only decode isolated words (Feely, 1943), the first use of a more or less sophisticated cipher (Strong, 1945; Brumbaugh, 1977), a text in a vowel-less Ukrainian (Stojko, 1978) or the only surviving document of the Cathar movement (Levitov, 1987). No acceptable plaintext has ever been produced though.

Some interesting new insights into the manuscript were provided in the 70's by Prescott Currier, presenting some of his results at an informal Voynich manuscript symposium at the National Security Agency in Washington. Basing his findings on the statistical properties of the text, he suggested that the manuscript is written in two distinct "languages" which he simply called A and B. Each bifolio was written in one of the two, and bifolios in the same "language" were generally grouped together. Only in the herbal section there is a mixture of A and B folios. Based on the characteristics of the writing, he showed that the manuscript seems to have been written in two distinct "hands", and he even suggested there could be as much as five or even eight different hands. A significant feature is that the hand and language used on each folio are fully correlated. Currier's conclusion was that at least two people were involved in writing the Voynich manuscript, (which he considered a point against the "hoax theory" summarised below), although alternatively, the manuscript could have been written by one person, in two distinct periods.

Due to the lack of success in the decipherment, a number of people have proposed that the manuscript is a "hoax". The manuscript could either be a 16th century forgery, to be sold for a hefty sum to emperor Rudolf II, who was interested in rare and unusual items (Brumbaugh, 1977, deriving from earlier unpublished theories), or a more recent one by W. Voynich himself (Barlow, 1986). The latter is effectively excluded both by expert dating of the manuscript, and by the evidence of its existence prior to 1887.

One problem with the earlier hoax theory is that, as will be shown, certain word statistics (Zipf's laws) found in the manuscript are characteristic of natural languages. In other words, it is unlikely that any forgery from 16th century would "by chance" produce a text that follows Zipf's laws (first postulated in 1935).

Since 1990, a multidisciplinary group of varying size, generally between 100 and 200 individuals, dispersed all around the globe and connected through the Internet, has maintained an electronic mail forum on the decipherment of the Voynich manuscript. This has led to a lively exchange of ideas and the definition of two main goals: a machine readable transcription of the manuscript text and the study of the text through numerical experiments.

In parallel, two new hypotheses about the Voynich MS were proposed. One Russian researcher suggested that the text of the Voynich MS is in Manchurian. Early 2004, the English psychologist Gordon Rugg suggested that the text has been generated mechanically using a Cardan grille, and that the text is meaningless. Despite his incomplete findings, this has received a lot of attention in the popular press, where his hypothesis is incorrectly presented as 'proven'.

In 2005, two Germans proposed a mystical interpretation of the Voynich MS, where every letter in the manuscript is to be translated to a word or 'principle' (for lack of a better term). This translation is presented 'as is', without justification or explanation and is therefore completely unverifiable.