Ordained in 1652, Molinos in 1663 was sent to Rome. There, in 1675, he published his Spiritual Guide, a small handbook teaching that Christian perfection is achieved by a mixture of contemplation and divine assistance. Molinos believed that men must banish their individual wills so that God's will can work unhampered within them.

The Guide caused a sensation; but in 1685, at the height of Molinos' influence and when his friend Innocent XI was pope, Molinos was arrested by the papal police, tried, and sentenced to life imprisonment for heresy.

Because the doctrines that resulted in his condemnation cannot be found in the Guide, this abrupt reversal of opinion is attributed to the discovery of personal immorality on the part of Molinos, the exact nature of which remains locked in the files of the Congregation for the Doctrine of the Faith. Some 20,000 of his letters were examined, and he and numerous witnesses were interrogated, resulting in the condemnation (1687) by Innocent of 68 propositions embodying Molinos' doctrine. In the “Summation” of his trial, Molinos defended sexual aberrations committed by himself and his followers as sinless, purifying acts caused by the devil. He claimed they were passively allowed in order to deepen a quiet repose in God. Still, he admitted being wrong and offered no further defense. He died in prison. His “Summation” is preserved in the Vallicellian Library in Rome, and his letters are in the archives of the Congregation for the Doctrine of the Faith.