Adapters are multidomain molecules that recruit effector proteins during signal transduction by immunoreceptors and integrins. The absence of these scaffolding molecules profoundly affects development and function of various hematopoietic lineages, underscoring their importance as regulators of signaling cascades. An emerging aspect of the mechanism by which engaged immunoreceptors and integrins transmit signals within the cell is by differential usage of various adapters that function to nucleate formation of distinct signaling complexes in a specific location within the cell. In this review, we discuss the mechanisms by which adapter proteins coordinate signal transduction with an emphasis on the role of subcellular compartmentalization in adapter function.