Excess MMP proteolytic activity has been associated with a wide variety of pathological conditions such as arthritis, cancer and heart failure. The potential utility of MMP inhibitors as therapeutic interventions in these diverse and important disease states has led to an intense effort toward the development of such inhibitors. The first generation of compounds were peptide-like broad spectrum inhibitors, active against a broad range of MMPs. However, the induction of musculoskeletal side effects seen in clinical trials with these agents has emphasized the need for a better understanding of the role that each of the MMPs plays in normal tissue turnover and disease progression. Advances in our ability to engineer and synthesize selective inhibitors as well as the discovery of small molecule, non-peptidic inhibitors has spurred an intense effort to identify potent and bioavailable second generation compounds. There are now several such compounds targeted against various subsets of the MMPs in clinical development. This review will focus on the design and structure activity relationships of these second generation compounds.