Herein we report the generation of mice lacking the ubiquitously expressed Janus kinase, Jak1. Jak1-1mice are runted at birth, fall to nurse, and die perinatally. Although Jak1-/- cells are responsive to many cytokines, they fall to manifest biologic responses to cytokines that bind to three distinct families of cytokine receptors. These include all class II cytokine receptors, cytokine receptors that utilize the γ(o) subunit for signaling, and the family of cytokine receptors that depend on the gp130 subunit for signaling. Our results thus demonstrate that Jak1 plays an essential and nonredundant role in promoting biologic responses induced by a select subset of cytokine receptors, including those in which Jak utilization was thought to be nonspecific.