Cold shock domain (CSD)-containing proteins have been found in all three domains of life and function in a variety of processes that are related, for the most part, to post-transcriptional gene regulation. The CSD is an ancient β-barrel fold that serves to bind nucleic acids. The CSD is structurally and functionally similar to the S1 domain, a fold with otherwise unrelated primary sequence. The flexibility of the CSD/S1 domain for RNA recognition confers an enormous functional versatility to the proteins that contain them. This review summarizes the current knowledge on eukaryotic CSD/S1 domain-containing proteins with a special emphasis on UNR (upstream of N-ras), a member of this family with multiple copies of the CSD.