Mitogen‐activated protein kinase (MAPK) pathways constitute a large modular network that regulates a variety of physiological processes, such as cell growth, differentiation, and apoptotic cell death. The function of the ERK pathway has been depicted as survival‐promoting, in essence by opposing the proapoptotic activity of the stress‐activated c‐Jun NH₂‐terminal kinase (JNK)/p38 MAPK pathways. However, recently published work suggests that extracellular regulated kinase (ERK) pathway activity is suppressed by JNK/p38 kinases during apoptosis induction. In this review, we will summarize the current knowledge about JNK/p38‐mediated mechanisms that negatively regulate the ERK pathway. In particular, we will focus on phosphatases (PP2A, MKPs) as inhibitors of ERK pathway activity in regulating apoptosis. A model proposed in this review places the negative regulation of the ERK pathway in a central position for the cellular decision‐making process that determines whether cells will live or die in response to apoptosis‐promoting signals. In addition, we will discuss the potential functional relevance of negative regulation of ERK pathway activity, for physiological and pathological conditions (e.g., cellular transformation). ‐ Junttila, M.R., Li, S.‐P., Westermarck, J. Phosphatase‐mediated crosstalk between MAPK signaling pathways in the regulation of cell survival. FASEB J. 22, 954–965 (2008)