Control of IFN-γ-secreting T helper (Th) 1 cells prevents autoimmunity and immunopathology during infection. IL-10-mediated suppression of Th1 cells is achieved not only through IL-10 produced extrinsically, but also through a negative feedback loop that induces "intrinsic" IL-10 expression in cells also expressing IFN-γ, during Th1 lineage differentiation. Targeting this Th1 cell IFN-γ to IL-10 switching is a tantalising prospect for developing therapeutics for Th1-mediated diseases. In this review, the molecular pathways that regulate IFN-γ versus IL-10 expression in Th1 cells are examined, with focus on the role of complement regulator and T cell co-stimulatory molecule CD46, and also discussed are challenges and controversies in the field.