SOCS proteins are regulators of various signal transduction cascades that are essential to normal physiology. Important advances have been made in understanding their mode of action. However, unresolved issues include the involvement of SOCS in the modulation of specific pathways and the mechanisms controlling stability and regulation of these proteins. The importance of this is underscored by the contribution of inappropriately regulated SOCS activity to several pathologies including cancer and inflammatory diseases. This work provides further insights in the role of SOCS proteins in different signalling pathways such as leptin signal transduction. The hormone leptin emerged as a key player in body weight regulation but it also has peripheral effects on diverse body functions. In the second part of this book novel roles for the SOCS box domain in the cross- regulation of other SOCS proteins and in substrate binding are reported. This work should help to further understand the mechanisms underlying SOCS actions. Undoubtedly, knowledge of how SOCS proteins are regulated may lead to development of potent therapeutic options in the treatment of several disorders.