SOCS3 is an inducible negative feedback inhibitor of cytokine signaling. Conditional deletion of SOCS3 in mice using the Cre-lox system has now been applied to a range of cell types in the steady-state and under inflammatory, pathogenic, or tumorigenic stress, with the resulting phenotypes demonstrating the effects of SOCS3 in physiological and disease contexts. Together with recent structural and biochemical studies on the mechanisms of SOCS3 binding to cytokine receptors and associated kinases, we now have a better understanding of the non-redundant roles of SOCS3 in the inhibition of cytokine signaling via the receptors gp130, G-CSFR, leptinR, and IL-12Rβ. This review discusses the known functional activities of SOCS3 in fertility and development, inflammation, innate and adaptive immunity, and malignancy as determined by genetic studies in mice.