p38 MAP kinases are activated by many types of environmental stress, inflammatory cytokines and apoptosis inducers, although sometimes may have other functions unrelated to stress, such as the regulation of cell proliferation, differentiation and motility in particular cell types. We have found that p38a, the p38 MAP kinase family member that is expressed ubiquitiously at higher levels, plays an important role in tumor suppression by inducing apoptosis. In particular, p38a detects the production of reactive oxygen species (ROS) by oncogenes and triggers apoptosis in cells with tumorigenic potential. At later stages of the tumorigenic process, however, the interplay between p38a, ROS and apoptosis is different. Thus, established human cancer cell lines have developed mechanisms to interfere with the apoptotic effect of p38a in response to ROS, which results in the accumulation of high levels of oxidative stress and enhanced tumorigenicity. Interestingly, cancer cells with high ROS levels (due to p38a downregulation) appear to be hyper-sensitised to apoptosis induced by cytotoxic agents. Finally, p38a activity has been recently correlated with the enhanced malignancy of certain types of human tumors, in contrast with the negative role of this signalling pathway in cancer initiation as an oxidative stress sensor. We will discuss results on how p38a contributes to human cancer progression.