Microsystems have become an increasingly important part of medical technology in many areas of diagnostics, drug delivery, bioelectronics, medical devices, implants, organ-on-a-chip devices, and others. Microdevice materials that interface with biological fluids, cells, and tissues must be tailored to ensure biocompatibility and desired functioning while avoiding negative responses. There are numerous factors to consider related to biointeractions with materials, including the biological environment, the contact time, and the size of device structures, among others. The host response to biomaterials includes protein adsorption, cell adhesion, and inflammation, and an enhanced understanding of these is essential to ensure biocompatibility. Since these interactions occur at the surface of materials and dictate the biological response, modifying the surface is a key strategy for improving microdevices. Surface modification approaches that will be discussed include those that are physical, chemical and biological. Physical attachment of polymers and proteins, plasma treatment and self-assembled monolayers are all straightforward modification methods that are commonly applied. Nanostructuring to increase the active surface area and modify the surface energy shows considerable promise. Altering the surface chemistry of the device can be achieved by grafting-to and grafting-from methods to graft polymers to the surface and antifouling strategies to reduce nonspecific adsorption of biomolecules. Bioactive approaches provide the opportunity to better mimic physiological functionality by attaching peptides, proteins and other molecules and through immunomodulatory material design. With ongoing advances in microsystems combined with the complexities of the biointeractions occurring at the surface of materials, continued efforts are needed for the development of biomaterials and surface modification processes that can enhance microdevice biocompatibility.