The enzymes of the protein disulfide isomerase (PDI) family are thiol-disulfide oxidoreductases of the endoplasmic reticulum (ER). They contain a CXXC active-site sequence where the two cysteines catalyze the exchange of a disulfide bond with or within substrates. The primary function of the PDIs in promoting oxidative protein folding in the ER has been extended in recent years to include roles in other processes such as ER-associated degradation (ERAD), trafficking, calcium homeostasis, antigen presentation and virus entry. Some of these functions are performed by non-catalytic members of the family that lack the active-site cysteines. Regardless of their function, all human PDIs contain at least one domain of approximately 100 amino acid residues with structural homology to thioredoxin. As we learn more about the individual proteins of the family, a complex picture is emerging that emphasizes as much their differences as their similarities, and underlines the versatility of the thioredoxin fold. Here, we primarily explore the diversity of cellular functions described for the human PDIs.