50 years ago Isaacs and Lindenmann (1) first described interferons (IFNs)2 as founding members of the cytokine family. Over the next 25 years, these and several other four-helix bundle cytokines were characterized. The subsequent 25 years witnessed an exponential growth in number of four-helix bundle cytokines and their corresponding receptors. The early availability of recombinant IFNs afforded an opportunity to investigate how cytokines induce gene expression, culminating in the identification of the JAK-STAT signaling paradigm (see Fig. 1). Subsequent studies identified 7 STATs and 4 JAKs, providing important insight into how the ~50 members of the four-helix bundle cytokine family transduce their potent biological responses. This review will briefly summarize this signaling paradigm (reviewed in Refs. 2¿5) and then focus on STAT-dependent transcription.