The pimelodid genus Hypophthalmus is a small group of pelagic and planktivorous catfishes that are abundant and variously distributed in the lowland river basins of the Amazon, Parnaíba, Orinoco, Guianas and Paraná. Since their earliest published descriptions, commencing over 190 years ago with H. edentatus Spix and Agassiz 1829, the taxonomy and nomenclature of Hypophthalmus species have been confused and unresolved. In this study, four of the six available species names are validated and two new species are described. Newly discovered characters of the vertebral column, circumoral barbels, pelvic fins, and lateralis sensory canals provide strong support and diagnostics for species and species-groups. A key to species, anatomical descriptions, notes on identification of small juveniles and phylogenetic interrelationships are included. A lectotype is designated for Hypophthalmus marginatus and nominal Hypophthalmus longifilis, respectively.