For the sixteenth century humanist, Christianity was tied to Antiquity through hidden strands that included mythology, magic, cosmology, and alchemy. The Ancients were credited with a fabulous wealth of hidden knowledge secretly passed down through carefully guarded channels. Exemplifying this secret knowledge are the messianic prophecies of the Sibyls, a prime instance of the Renaissance Christian reverence toward ancient mystic voices. Thus, Michelangelo painted five of the Sibyls alongside several Old Testament prophets on the ceiling of the Sistine Chapel. Orlande de Lassus' Prophetiae Sibyllarum, based on Latin writings inspired by the Sibyls, differs from the rest of his oeuvre by virtue of its incredible harmonic language and intricate voice leading. Furthermore, in the spirit of the humanists' interest in occult knowledge, the Prophetiae Sibyllarum were performed for select insiders only, and were not published until after the composer's death.

An exact composition date is not known. However, evidence suggests that in the early 1550s Lassus would have been witness to the great debate about chromaticism taking place at the time, and as a young composer of barely 20 years, sided with more musically progressive parties. A Latin print of the Sibylline Prophecies was released in 1555, suggesting that perhaps the harmonically and intellectually ambitious Lassus combined his interest in radical chromaticism and Christian mysticism to produce the Prophetiae Sibyllarum in the middle or late 1550s. So extreme was the experimentation found in these settings that Lassus seems to have abandoned it.

Following a prologue, there are musical renditions of verses by each of 12 Sibyls. The musical prologue, while explaining the chromatic style in which the subsequent prophecies will be set, follows a dizzying harmonic trajectory in which virtually every word is accompanied by a move to an unexpected chord. At the same time, the individual voices proceed in a more or less logical melodic fashion. However, it should be pointed out that modern singers face the challenge of singing in just intonation (as opposed to equal temperament, the current tuning system used in Western classical music). Sung in a "modern" fashion, the work drastically slides out of tune. The extreme chromaticism of this composition has prompted certain scholars to suggest links between music and alchemy. After all, the alchemist also practices chromaticism—the Greek word chroma means "color." A successful alchemical transfiguration was signaled by particular observable changes in the color of the mixture. The analogy between alchemy and Lassus' Prophetiae Sibyllarum seems compelling: only when the intricate individual lines are carried out accurately and with intonational precision does the chromaticism take on the desired harmonic hue.

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