Cell to matrix adhesion regulates cellular homeostasis in multiple ways. Integrin attachment to the extracellular matrix mediates this regulation through direct and indirect connections to the actin cytoskeleton, growth factor receptors, and intracellular signal transduction cascades. Disruption of this connection to the extracellular matrix has deleterious effects on cell survival. It leads to a specific type of apoptosis known as anoikis in most non-transformed cell types. Anchorage independent growth is a critical step in the tumorigenic transformation of cells. Thus, breaching the anoikis barrier disrupts the cell's defenses against transformation. This review examines recent investigations into the molecular mechanisms of anoikis to illustrate current understanding of this important process.