Insect odorant-binding proteins (OBPs) are thought to facilitate the delivery of hydrophobic odorants, such as sex pheromones or food odors, to receptors on sensory neurons. Increasingly, OBP family members are also being found in non-sensory tissues where they might carry other types of small hydrophobic molecules. They are identifiable by four or six conserved Cys residues and contain six alpha-helices which enclose a hydrophobic ligand-binding pocket. Through exhaustive BLAST searches we have increased the total number of OBPs identified in Drosophila melanogaster to 38, and have amplified the DNA complementary to RNA corresponding to 21 of these by reverse transcriptase polymerase chain reaction. Isoforms frequently share less than 30% amino acid identity and appear to have radically changed since the separation of the major insect orders. However, their sequences are consistent with known OBP structures. Most are located in clusters of between four and 14 genes and several were unusual in that they contained additions, deletions, or fusions. These hexa-helical insect OBPs are structurally unrelated to the functionally analogous lipocalin-like beta-barrel OBPs of vertebrates. As only two lipocalin-like proteins have been found in D. melanogaster, these helical proteins appear to be the dominant carrier of small hydrophobic molecules in insects.