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Disabled-2 (Dab2/DOC-2) is a mitogen-responsive adaptor protein required for multiple cellular functions. It is involved in many signaling pathways and plays an integral role in vesicular uptake and trafficking, modulating immune function, protein-protein interactions, cellular homeostasis and differentiation, oncogenesis, and inflammatory processes in organ systems. It contains domains for binding to NPXY motif-containing and SH3 domain-containing adapter proteins, phosphoinositides, glycoprotein 100 (gp100, or megalin), integrins, clathrin, and myosin VI. However, the molecular mechanism(s) of Dab2's biological function still remain to be elucidated. In this review, we provide an extensive up-to-date understanding of the function of Dab2 and its regulation in cardiovascular diseases, immune disorders, tumorigenesis, and central nervous system disorders.