The p38 mitogen-activated protein kinase (p38MAPK) signal transduction pathway is an important regulator of cell processes, whose deregulation leads to the development and progression of cancer. Defining the role of each p38MAPK family member in these processes has been difficult. To date, most studies of the p38MAPK pathways focused on function of the p38α isoform, which is widely considered to negatively regulate malignant transformation; nonetheless, few reports address the p38γ and p38δ isoforms. Here, we used embryonic fibroblasts derived from mice lacking p38γ or p38δ and show evidence that these isoforms participate in several processes involved in malignant transformation. We observed that lack of either p38γ or p38δ increased cell migration and metalloproteinase-2 secretion, whereas only p38δ deficiency impaired cell contact inhibition. In addition, lack of p38γ in K-Ras-transformed fibroblasts led to increased cell proliferation as well as tumorigenesis both in vitro and in vivo. Our results indicate that p38γ and p38δ have a role in the suppression of tumor development.