The mammary gland is a highly organized tissue, containing ductal structures, secretory alveolar units, and a supporting stroma. The organization of the epithelial cells within the tissue depends upon cell-cell adhesion as well as cell interactions with the extracellular matrix that underlies the epithelial units and makes up most of the organization of the stroma. Adhesion to the extracellular matrix is mediated by a class of heterodimeric transmembrane receptors called integrins, which cluster at focal adhesions. Integrins link the matrix with an intracellular structural scaffold, the cytoskeleton, as well as with signaling enzymes that direct cell survival, proliferation, differentiation, and migration. Two key enzymes that are recruited to sites of integrin clustering are focal adhesion kinase and integrin-linked kinase. Both enzymes are involved with communication downstream of integrins and have key roles in regulating cell behavior. This review will focus on what is known about focal adhesion kinase and integrin-linked kinase signaling and will discuss current evidence about their role in mammary gland biology and neoplasia.