The p38 proteins are an evolutionally conserved family of mitogen-activated protein kinases (MAPK). Recent studies have led to progress in our understanding the roles of p38 MAPK in regulation of tumorigenesis through key cellular growth-control mechanisms. Along with the previously well-characterized proapoptotic functions, new data highlight the critical contributions of p38 MAPK in the negative regulation of cell cycle progression. This review will focus on the ability of p38 MAPK to positively regulate several tumor suppressor (p53- and Rb-dependent) pathways and to attenuate oncogenic (Cdc25A and Cdc25B phosphatases) signals. The concept of p38 MAPK as a potential tumor suppressor will be developed.