Reciprocal regulation of tyrosine phosphorylation by protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs) is central to normal immune cell function. Disruption of the equilibrium between PTK and PTP activity can result in immunodeficiency, autoimmunity, or malignancy. Src family kinases (SFKs) play a central role in both immune cell function and disease due to their proximal position in numerous signal transduction cascades including those emanating from integrin, T and B-cell antigen receptors, Fc, growth factor, and cytokine receptors. Given that tight regulation of SFKs activity is critical for appropriate responses to stimulation of these various signaling pathways, it is perhaps not surprising that multiple PTPs are involved in their regulation. Here, we focus on the role of three phosphatases, CD45, CD148, and LYP/PEP, which are critical regulators of SFKs in hematopoietic cells. We review our current understanding of their structures, expression, functions in different hematopoietic cell subsets, regulation, and putative roles in disease. Finally, we discuss remaining questions that must be addressed if we are to have a clearer understanding of the coordinated regulation of tyrosine phosphorylation and signaling networks in hematopoietic cells and how they could potentially be manipulated therapeutically in disease.