The impact of cell adhesion in the pathobiology of tumors has been studied almost exclusively in the context of invasion, angiogenesis, and metastasis. Here we review data supporting a major role for cell-cell adhesion in the regulation of intrinsic or acquired resistance of solid tumors to various anticancer therapeutics. Cell-cell interactions are known to protect cells from apoptosis, and may help to explain chemoresistance of solid tumors. Recent data implicates p27KIP1, a cyclin-dependent kinase inhibitor, as a possible mediator of adhesion-dependent drug resistance. A model is described whereby cell-cell interactions signal the upregulation of p27, which in turn causes growth arrest in the G1 phase of the cell cycle and resistance to apoptosis induced by anticancer agents that target rapidly dividing cells. We focus on E-cadherin, a homophilic cell-cell adhesion molecule capable of upregulating p27, as one potential mediator of intrinsic resistance of carcinomas. A clearer understanding of how cell-cell adhesion suppresses cell growth and apoptosis should aid in the development of novel, more effective anticancer strategies.