ABSTRACT Cl− intracellular channels (CLICs) are a family of six evolutionary conserved cytosolic proteins that exist in both soluble and membrane-associated forms; however, their functions have long been elusive. Soluble CLICs adopt a glutathione S-transferase (GST)-fold, can induce ion currents in artificial membranes and show oxidoreductase activity in vitro, but there is no convincing evidence of CLICs having such activities in vivo. Recent studies have revealed a role for CLIC proteins in Rho-regulated cortical actin dynamics as well as vesicular trafficking and integrin recycling, the latter of which are under the control of Rab GTPases. In this Commentary, we discuss the emerging roles of CLIC proteins in these processes and the lessons learned from gene-targeting studies. We also highlight outstanding questions regarding the molecular function(s) of these important but still poorly understood proteins.