Microfluidic systems allow small volumes of liquids to be manipulated, either by being passed through channels or moved around as liquid droplets. Such systems have been developed to separate, purify, analyze, and deliver molecules to reaction zones. Although volumes are small, reaction rates, catalysis, mixing, and heat transfer can be high, enabling the accurate sensing of tiny quantities of agents and the synthesis of novel products. The incorporation of multiple components, such as pumps, valves, mixers, and heaters, onto a single microfluidic platform has brought about the field of lab-on-a-chip devices or micro total analysis systems (μTAS). Although used in the research laboratory for numerous years, few of these devices have made it into the commercial market, due to their complexity of fabrication and limited choice of material. As the dimensions of these systems become smaller, interfacial interactions begin to dominate in terms of device performance. Appropriate selection of bulk materials, or the application of surface coatings, can allow control over surface properties, such as the adsorption of (bio)molecules. Here we review current microfluidic technology in terms of biocompatibility issues, examining the use of modification strategies to improve device longevity and performance.