A predominant characteristic of metastatic cells is the ability to invade host tissues and establish distant metastatic foci. Release of metastatic cells from a primary tumor results from disruption of tissue architecture and requires reversible modulation of cell-matrix and cell-cell contacts, cytoskeletal rearrangement, and acquisition of enhanced proteolytic potential. Malignant cells produce a spectrum of extracellular proteinases including matrix metalloproteinases (MMPs) that process extracellular matrix components, cell surface proteins, and immune modulators. Dysregulated proteolysis has been implicated in tumor invasion and metastasis in multiple model systems. This review will focus on data that highlight the influence of cell-matrix and cell-cell interactions and their associated signal transduction pathways on proteinase regulation. These data highlight cell adhesion signaling as a mechanism for a versatile cellular proteolytic response to changing microenvironmental cues.