To assess the role of the Janus kinase (Jak) family member Tyk2, we have generated Tyk2^-/- mice. In contrast to other Jaks, where inactivation leads to a complete loss of the respective cytokine receptor signal, Tyk2^-/- mice display reduced responses to IFNα/β and IL-12 and a selective deficiency in Stat3 activation in these pathways. Unexpectedly, IFNγ signaling is also impaired in Tyk2^-/- mice. Tyk2^-/- macrophages fail to produce nitric oxide upon lipopolysaccharide induction. Tyk2^-/- mice are unable to clear vaccinia virus and show a reduced T cell response after LCMV challenge. These data imply a selective contribution of Tyk2 to the signals triggered by various biological stimuli and cytokine receptors.