The SH2 domain-containing phosphatases, SHP-1 and SHP-2, are well-studied cytosolic tyrosine phosphatases that share many structural and regulatory features. They both have two tandem SH2 domains at the N-terminus, followed by a catalytic domain, and an inhibitory C-terminus. Despite their structural similarity, the enzymes appear to have different physiological roles and exhibit different expression patterns. SHP-1 is highly expressed in hematopoietic tissues, and in general has a negative impact on lymphocyte signaling. In contrast, SHP-2 is widely expressed, and in general promotes signaling pathways that lead to differentiation, cell growth, or migration.