Adapter molecules are multidomain proteins lacking intrinsic catalytic activity, functioning instead by nucleating molecular complexes during signal transduction. The SLP-76 family of adapters includes SH2 domain-containing leukocyte phosphoprotein of 76kDa (SLP-76), B cell linker protein (BLNK), and cytokine-dependent hematopoietic cell linker (Clnk). These proteins are critical for integration of numerous signaling cascades downstream of immunotyrosine-based activation motif (ITAM)-bearing receptors and integrins in diverse hematopoietic cell types. Mutations in genes encoding SLP-76 family adapters result in severe phenotypes, underscoring the critical role these proteins play in cellular development and function by directing formation of signaling complexes in a temporally- and spatially-specific manner.