Tissues are three-dimensional (3D) entities as is the tumor that arises within them. Though disaggregated cancerous tissues have produced numerous cell lines for basic and applied research, it is generally agreed that these lines are poor models of in vivo phenomena. In this review we focus on in vitro 3D models used in cancer research, particularly their contribution to molecular studies of the early stages of metastasis, angiogenesis, the tumor microenvironment, and cancer stem cells. We present a summary of the various formats used in the field of tissue bioengineering as they apply to mechanistic modeling of cancer stages or processes. In addition we list studies that model specific types of malignancies, highlight drastic differences in results between 3D in vitro models and classical monolayer culturing techniques, and establish the need for standardization of 3D models for meaningful preclinical and therapeutic testing. © 2011 Wiley Periodicals, Inc.