Recent advances in the study of CD22 indicate a complex role for this transmembrane glycoprotein member of the immunoglobulin superfamily in the regulation of B lymphocyte survival and proliferation. CD22 has been previously recognized as a potential lectin-like adhesion molecule that binds alpha2,6-linked sialic acid-bearing ligands and as an important regulator of B-cell antigen receptor (BCR) signaling. However, genetic studies in mice reveal that some CD22 functions are regulated by ligand binding, whereas other functions are ligand-independent and may only require expression of an intact CD22 cytoplasmic domain at the B-cell surface. Until recently, most of the functional activity of CD22 has been widely attributed to CD22's ability to recruit potent intracellular phosphatases and limit the intensity of BCR-generated signals. However, a more complex role for CD22 has recently emerged, including a central role in a novel regulatory loop controlling the CD19/CD21-Src-family protein tyrosine kinase (PTK) amplification pathway that regulates basal signaling thresholds and intensifies Src-family kinase activation after BCR ligation. CD22 is also central to the regulation of peripheral B-cell homeostasis and survival, the promotion of BCR-induced cell cycle progression, and is a potent regulator of CD40 signaling. Herein we discuss our current understanding of how CD22 governs these complex and overlapping processes, how alterations in these tightly controlled regulatory activities may influence autoimmune disease, and the current and future applications of CD22-directed therapies in oncology and autoimmunity.