Since their first introduction, polyacrylamide hydrogels have proven to be very useful for studies of mechanical interactions at the cell-substrate interface. In this chapter, we briefly review the basic concepts of this method and provide a series of modifications that have evolved since its inception. In addition, we have described several alternative uses of polyacrylamide hydrogels that have emerged for the study of cellular mechanics. Our intention is to provide users of this gel system with a number of improved and tested options as this method advances toward optimization.