Herein we review studies demonstrating resistance manifested at the multicellular level, a phenomenon referred to as intrinsic or acquired multicellular resistance (MR). In addition, due to the fact that such resistance can be recapitulated in vitro only when cells are adhered to one another in a three-dimensional culture context, we examine the roles of cell adhesion molecules and how they may contribute directly or indirectly to MR. Finally, we suggest an experimental approach to circumvent MR in the treatment of advanced, aggressive ascites tumors.