The nucleophosmin (NPM)/nucleoplasmin family of nuclear chaperones has three members: NPM1, NPM2, and NPM3. Nuclear chaperones serve to ensure proper assembly of nucleosomes and proper formation of higher order structures of chromatin. In fact, this family of proteins has such diverse functions in cellular processes such as chromatin remodeling, ribosome biogenesis, genome stability, centrosome replication, cell cycle, transcriptional regulation, apoptosis, and tumor suppression. Of the members of this family, NPM1 is the most studied and is the main focus of this review. NPM2 and NPM3 are less well characterized, and are also discussed wherever appropriate. The structure-function relationship of NPM proteins has largely been worked out. Other than the many processes in which NPM1 takes part, the major interest comes from its involvement in human cancers, particularly acute myeloid leukemia (AML). Its significance stems from the fact that AML with mutated NPM1 accounts for ∼30% of all AML cases and usually has good prognosis. Its clinical importance also comes from its involvement in virus replication, particularly in the era of outbreaks of infectious diseases.