This article considers the role of grotesques in sixteenth-century culture. Ornamental frescoes demonstrate the attractiveness of an “imagery of ambiguity”, which the article investigates as characteristic of wider culture at the time. Themes of fluctuation became prominent in artists’ subjects, forms, techniques, and colors; in individuals’ thinking regarding personality and identity; and in various genres and cultural fields. I argue that aspects of grotesques in art can shed light on sixteenth-century culture, and vice versa, given that ideas and mental habits concerning materiality inform the production of images. By presenting various examples of the approach to and understanding of materials, I delineate the contours of some fundamental conditions for image-making and characterize that which distinguishes this period within the history of art