p38 is a MAPK that has been shown to induce a wide variety of biological effects in cell culture in response to a wide range of stimuli. These effects are dependent not only on the stimuli, but also on the cellular context, resulting in a bewildering array of possibilities. For example, p38 was shown to induce apoptosis in some cells, but prevent apoptosis in others. Similarly opposed effects had been observed with respect to cell cycle regulation. The role of p38 in inflammatory disease has been appreciated from the beginning, since it was initially identified as an cytokine inducer. More recently, p38 function has been evaluated in vivo, and through these studies p38 has emerged as an important regulator of both embryonic development and cancer progression. This review will focus on these in vivo studies in an effort to provide perspective on p38 biologically and as a pharmacological target.