The surface of a biomaterial plays a critical role in the success of an implant. Much effort is currently being focused on controlling the chemistry at biomaterial surfaces to ensure favorable results in vivo. The successful tailoring of the surface chemistry will require a detailed surface characterization to verify that the desired changes have been made. This will include the ability to determine the composition, structure, orientation, and spatial distribution, of the molecules and chemical structures on the surface. TOF-SIMS is a powerful surface characterization technique that is able to address these requirements through both spectral analysis and direct chemical state imaging. The flexibility of the TOF-SIMS technique, and the wealth of data produced have generated much interest in its use for biomaterial characterization. This review discusses the strengths, weaknesses, and challenges of static TOF-SIMS for biomaterial surface characterization. First the basic principles of TOF-SIMS are introduced, giving an overview of the technique. Next, sample type, and other sample considerations are discussed. Then data interpretation is overviewed using examples from both spectral and imaging data. Finally, quantitative SIMS analysis is discussed and an outlook for TOF-SIMS analysis of biomaterials will be given.