Paintings can be interpreted as the product of the complex neural machinery that translates physical light signals into behavior, experience, and emotion. The brain mechanisms responsible for vision and perception have been sculpted during evolution and further modified by cultural exposure and development. By closely examining artists’ paintings and practices, we can discover hints to how the brain works, and achieve insight into the discoveries and inventions of artists and their impact on culture. Here, I focus on an integral aspect of color, color contrast, which poses a challenge for artists: a mark situated on an otherwise blank canvas will appear a different color in the context of the finished painting. How do artists account for this change in color during the production of a painting? In the broader context of neural and philosophical considerations of color, I discuss the practices of three modern masters, Henri Matisse, Paul Cézanne, and Claude Monet, and suggest that the strategies they developed not only capitalized on the neural mechanisms of color, but also influenced the trajectory of western art history.