Within the last 20 years, multiple novel intracellular signal transduction pathways, downstream of plasma membrane receptors, have been discovered. These pathways have been linked to the regulation of diverse cellular events such as proliferation, senescence, differentiation and apoptosis. This review will focus upon the roles of signaling by the ErbB receptor tyrosine kinase family (ErbB1-4) in the survival of cells in response to cytotoxic stresses. In addition, plasma membrane-to-nucleus signaling pathways downstream of these receptors, such as mitogen activated protein kinase (MAPK) and phosphatidyl inositol 3-kinase (PI3K), in the control of cell survival will be discussed. Recent evidence suggests that signaling by the MAPK and PI3K pathways can both enhance proliferation as well as protect cells from apoptosis. We describe potential mechanisms by which modulation of pathway activities following inhibition of ErbB receptor function may alter the sensitivity of cells to toxic insults, leading to increased apoptosis and loss of clonogenic survival.