SLP76 and SLP65 are adaptor proteins that lack intrinsic enzymatic activity but contain multiple protein-binding domains. These proteins are essential for signalling downstream of integrins and receptors that contain immunoreceptor tyrosine-based activation motifs. The absence of these adaptor proteins profoundly affects various lineages in the haematopoietic compartment and severely compromises vascular development, highlighting their importance as regulators of signalling cascades. In this Review, we discuss the role of SLP76 and SLP65 in several signalling pathways in haematopoietic cells, with an emphasis on recent studies that provide insight into their mechanisms of action.