Cells respond to three main categories of physicochemical cues: chemical, topographical, and mechanical. While surface chemistry and topography have been studied extensively, substrate mechanics has only recently been appreciated. Recent technologies of creating surfaces with well-defined chemistry and topography combined with sensitive surface characterization techniques have unquestionably deepened our understanding of surface chemical and topographical effects on cell behavior. In contrast, much less is known about substrate mechanics effects on cell behavior. This talk discusses the types of substrata and characterization methods that have been used to investigate substrate mechanics effects on cell behavior. We also speculate on the relationships between changes in substrate elasticity that occur naturally in vivo (e.g. wound healing) and cellular response. We present recent developments in creating substrata with well-defined mechanical properties in our own laboratory and the major challenges and issues of determining whether substrate mechanics effects are a material-independent phenomenon. We also discuss the effects of combining multiple physicochemical cues on cell behavior. The use of model systems in which chemistry, topography, and mechanics can be independently controlled will facilitate the quest for design principles and material selection rules to control cell response.