<p>Normal epithelial cells detach from extracellular matrix during normal homeostasis by a selective process called epithelial extrusion. Thereafter, they undergo apoptosis, in a phenomenon called anoikis. Metastatic tumor cells, however, detach from normal epithelial tissues or primary tumors and survive in circulation, sometimes long enough to disseminate and colonize metastatic sites. The thirty years since the discovery of anoikis, exciting progress has been made in understanding anoikis mechanisms and the diverse mechanisms by which tumor cells evade or subvert them. Previous reviews have summarized earlier aspects of anoikis, including integrin-apoptosis signaling, Epithelial-Mesenchymal Transition and intracellular metabolism. Based on recently emerging work, we focus here on four issues that advance our conceptual understanding significantly: How do cytoskeleton and signaling interface so as to control anoikis? How is epithelial extrusion programmed in normal vs. cancer cells, upstream of anoikis? What is the role of translational regulation in anoikis? How do tumor cell-blood cell interactions affect anoikis? This review summarizes recent observations that inform these issues, and provides perspective on future problems to be investigated. </p>