This dissertation examines sixteenth-century Antwerp art in socio-historical context through the career of Jan Sanders van Hemessen (active by 1524–died after 1556), one of the most successful painters in Antwerp at a time when the port city was an international center for both art and commerce. Structured around four chapter-length case studies, the dissertation concludes with updated Checklists of Paintings and Technical Art Historical Appendices that enrich the first sustained investigation of Van Hemessen’s working process. Focusing on the painter’s signature large-scale, muscular figures, the study establishes the conditions of creation and reception ranging from artistic collaboration to the complex portrayals of gender and sexuality in novel religious iconographies and nascent genre imagery—a subject too often neglected in the literature to date. The first half of the dissertation reassesses how Van Hemessen’s religious paintings counterintuitively use a confrontational and theatrical compositional approach to train the perceptive viewer toward deeper inward contemplation and work on the self. In so doing, Chapters One and Two reframe art historical assumptions about how gender was figured and understood in iconic religious imagery, revealing more fluid and open avenues for conceiving of gendered embodied experience that were encouraged specifically in meditative devotional contexts. Chapters Three and Four reconsider how satirical or bawdy visual humor structured representations of difference, including religious difference. This second half of the project offers new critical insights concerning how references to artistic labor (and its effacement) by Van Hemessen interact with depictions of labor and leisure in his innovative genre imagery, notably of tax offices and brothels. Van Hemessen’s career clarifies how art embraced emerging values of the open market at the outset of the Reformation and in a time of emerging capitalism.