A recent cleaning of the painting, scientific examinations of it, the publication of new letters related to it, and studies of the prophetic culture in which it was produced all call for a reevaluation of the traditional interpretations of Raphael's portrait Leo X with Cardinals Giulio de' Medici and Luigi de' Rossi. After a close analysis of the major iconographic details in the painting, the strengths and weaknesses of the various secular and religious interpretations of the painting are reviewed. That the painting is primarily religious in theme with prophetic and devotional overtones is argued as the most reasonable interpretation, given the iconographic details and context.