Cold shock domain proteins are characterized by the presence of one or more evolutionarily conserved cold shock domains, which each possess two nucleic acid-binding motifs. These proteins exert pleiotropic functions in cells via their ability to bind single-stranded RNA and/or DNA, thus allowing them to serve as transcriptional as well as translational regulators. Not only can they regulate their own expression, but they also regulate the expression of a number of pro- and anti-inflammatory cytokines, as well as cytokine receptors, making them key players in the orchestration of inflammatory processes and immune cell phenotypes. To add to their complexity, the expression of cold shock domain proteins is induced by cellular stress. At least one cold shock domain protein is actively secreted and binds to specific cell surface receptors, thereby influencing the proliferative and migratory capacity of the cell. The presence of cold shock domain proteins in the blood and/or urine of patients with cancer or inflammatory disease, as well as the identification of autoantibodies directed against these proteins make them potential targets of therapeutic interest.