Combinatorial and high-throughput methods have been increasingly used to accelerate research and development of new biomaterials. These methods involve creating miniaturized libraries that contain many specimens in one sample in the form of gradients or arrays, followed by automated data collection and analysis. This article reviews recent advances in utilizing combinatorial and high-throughput methods to better understand cell–material interactions, particularly highlighting our efforts at the NIST Polymers Division. Specifically, fabrication techniques to generate controlled surfaces (2D) and 3D cell environments (tissue engineering scaffolds) as well as methods to characterize and analyze material properties and cell–material interactions are described. In conclusion, additional opportunities for combinatorial methods for biomaterials research are noted, including streamlined sample fabrication and characterization, appropriate and automated bioassays, and data analysis.