Over the last 10 years, there has been a dramatic increase in interest in the role of signaling pathways in governing neoplastic cell behavior. Much of this interest has focused on members of the MAPK3 pathways, which include the ERK, the JNK, also called the SAPK, and the p38 kinase modules (1, 2). Such signaling pathways regulate multiple biological activities, including cell proliferation, differentiation, cell cycle traverse, and survival, among others (3). Mechanistic insights into the roles of these signaling cascades in modulating neoplastic cell survival have emerged from studies investigating programmed cell death, or apoptosis. Although exceptions occur, the bulk of evidence suggests that activation of the ERK (MAPK) pathway increases, in an unknown way, the cell death threshold (4); conversely, activation of the JNK/SAPK and p38 kinase cascades are generally (although not universally) associated with enhanced activation of the apoptotic program (5). An alternative model suggests that cell-death decisions ultimately depend upon the dynamic balance between the outputs of pro-and antiapoptotic pathways. A corollary of these hypothetical models is that interruption (pharmacological or otherwise) of putatively cytoprotective signaling pathways in malignant cells could shift the balance away from survival toward cell death. The purpose of this brief overview is not to present a exhaustive review of MEK/MAPK inhibitors; instead, it is to provide a theoretical framework for attempts to understand the possible role of such agents as modulators of cytotoxic drug action. Included is speculation concerning the downstream effectors that may be involved in this phenomenon; in addition, a summary of interactions between MEK/MAPK inhibitors and selected cytotoxic agents is presented. We refer the reader to other reviews for a broader overview of this subject (6).