Cancer results from genetic alterations in intracellular signaling pathways, which normally orchestrate the execution of developmental programs and the organismic response to extrinsic factors. Mutations in upstream activators and components of the cytoplasmic (Ras-Raf MEK-ERK) cascade frequently occur in tumors. In vitro and in vivo studies have shown that isolated activation of this pathway is both, necessary and sufficient for transformation. During the last years two new groups of related kinases have joined the ranks of mitogen-activated protein kinases, stress-activated protein kinases/Jun N-terminal kinases and p38. Their activation not only occurs during cellular responses to unphysiological stimuli but also downstream of cytokine and pathogen receptors and has been observed in tumors. In this article we will review the role of stress kinases in cancer, and discuss the mechanisms through which they regulate the transformation process.