We present a molecular phylogenetic study of the major lineages of the Pimelodoidea, the second largest and most widespread clade of Neotropical catfishes, in which we examine the affinities of two incertae sedis genera, Conorhynchos and Phreatobius with respect to 24 pimelodoid terminals within the families Pimelodidae, Pseudopimelodidae and Heptapteridae. We include Diplomystes mesembrinus and 11 siluroid, non-pimelodoid taxa as outgroups. Data are more than six kilobases of aligned sequence from the rag1 and rag2 nuclear genes and 12S and 16S rDNA from the mitochondrial genome. Results provide strong support for the monophyly of Pimelodoidea, for the families Pimelodidae, Pseudopimelodidae and Heptapteridae individually, and for the interrelationships described in parenthetical notation as ((Conorhynchos, Heptapteridae), (Phreatobius, Pseudopimelodidae, Pimelodidae)). Within this latter group, analysis of the data using parsimony favors ((Phreatobius, Pseudopimelodidae), Pimelodidae), while Bayesian favors (Phreatobius, (Pseudopimelodidae, Pimelodidae)). However, comparison of tree length in parsimony and Bayes Factor comparisons shows that no resolution of this three-taxon statement is significantly better supported. We added the rag1 and rag2 sequences of taxa newly sequenced for this study to a previously published dataset of 111 catfish terminals. Fossil-calibrated, Bayesian relaxed clock analysis of divergence times indicate that pimelodoids are likely to have originated between 110 and 95 Ma in the Albian or Cenomanian and that the five major lines of pimelodoids split off soon afterward during a period of explosive diversification for siluroid catfishes.