p38α is a ubiquitous protein kinase strongly activated by stress signals, inflammatory cytokines, and many other stimuli, which has been implicated in the modulation of multiple cellular processes. There is good evidence in the literature that p38α plays an important tumor-suppressor role by interfering with malignant cell transformation. This is mainly based on the ability of the p38α pathway to regulate tissue homeostasis by integrating signals that balance cell proliferation and differentiation or induce apoptosis. However, recent reports have also illustrated protumorigenic functions for p38α. Thus, p38α signaling may facilitate the survival and proliferation of tumor cells contributing to the progression of some tumor types. In addition, p38α activation helps tumor cells to survive chemotherapeutic treatments. In all these cases, the inhibition of p38α has a potential therapeutic interest. Further elucidation of the context-dependent functions of p38α signaling in tumoral processes is of obvious importance for the use of inhibitors of this pathway in cancer therapy.