The majority of plant disease resistance proteins identified to date belong to a limited number of structural classes, of which those containing nucleotide-binding site (NBS) motifs are the most common. This study provides a detailed analysis of the NBS-encoding genes of the fifth sequenced angiosperm, Carica papaya. Despite having a significantly larger genome than Arabidopsis thaliana, papaya has fewer NBS genes. Nevertheless, papaya maintains genes belonging to both Toll/interleukin-1 receptor (TIR) and non-TIR subclasses. Papaya's NBS gene family shares most similarity with Vitis vinifera homologs, but seven non-TIR members with distinct motif sequence represent a novel subgroup. Transcript splice variants and adjacent genes encoding resistance-associated proteins may provide functional compensation for the apparent scarcity of NBS class resistance genes. Looking forward, the papaya NBS gene family is uniquely small in size but structurally diverse, making it suitable for functional studies aimed at a broader understanding of plant resistance genes.