© 2005 by Oxford University Press, Inc. All rights reserved. This chapter discusses the activation of the Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway and the mechanisms that are used to control the magnitude and duration of signaling. It focuses on the suppressor of cytokine signaling (SOCS) family of proteins that act in a negative feedback loop to extinguish signal transduction. It also briefly reviews the other major signalling pathways that are used by tumor necrosis factor (TNF) family members and members of the transforming growth factor (TGF) family. In addition, signaling by chemokines through G-protein-coupled chemokine receptors is described.