Cell-extracellular-matrix adhesion and communication are mediated by integrins and a complex network of proteins that link integrins to the actin cytoskeleton. In this article, I discuss recent evidence that indicates that PINCH-1 and integrin-linked kinase (ILK), which form a tight complex in cells, serve as one of the hubs in the integrin-actin network. This hub mediates many protein interactions with a wide range of affinities (K(D) ranging from >10(-3)M to <10(-7)M). Furthermore, many of these interactions are evolutionally conserved and functionally indispensable for maintaining the integrity of and signaling through the integrin-actin network. Consequently, loss of the PINCH-1-ILK complex is disastrous for embryogenesis in vertebrates and invertebrates. By contrast, aberrance of individual interactions contributes to diverse defects. Dissecting the interactions and functions that are mediated by the PINCH-1-ILK complex presents an exciting challenge and an opportunity to unravel the structure and functions of the integrin-actin network.