Disulfide bonds play an important role in the structure and function of membrane and secretory proteins. The formation of disulfide bonds in the endoplasmic reticulum (ER) of eukaryotic cells is catalyzed by a complex network of thiol-disulfide oxidoreductases. Whereas a number of ER-resident oxidoreductases have been identified, the function of only a few of them is firmly established. Recently, a selenocysteine-containing oxidoreductase, Sep15, has been implicated in disulfide bond assisted protein folding, and a role in quality control for this selenoprotein has been proposed. This review summarizes up-to-date information on the Sep15 family proteins and highlights new insights into their physiological function.