The subfamily Heteromyinae (spiny pocket mice) represents a well-defined monophyletic group within the rodent family Heteromyidae. Although 2 genera of spiny pocket mice, Heteromys and Liomys, are recognized in the subfamily, no phylogenetic analysis has demonstrated their reciprocal monophyly. A recent study using DNA-sequence data from the mitochondrial gene cytochrome b suggested that Liomys is paraphyletic but included few species of Heteromys. Here, we conduct phylogenetic analyses of the subfamily with dense taxonomic sampling using allozymic data from a previous study and external and cranial morphological data; our aim is to assess generic monophyly and elucidate phylogenetic structure within the genera, to the degree possible with these data. We also reidentify selected voucher specimens from the allozymic study. Parsimony-based analyses indicate 3 clades in the subfamily: (A) Liomys irroratus, L. pictus, and L. spectabilis; (B) L. adspersus and L. salvini; and (C) all examined species of Heteromys. However, the relationships among these clades are unresolved. The genus Heteromys is characterized by strong support and several unreversed morphological synapomorphies. In contrast, our analyses fail to indicate any synapomorphies for Liomys, but can neither demonstrate nor reject its monophyly. The 3 clades identified here match those recovered from a recent mitochondrial DNA–sequencing study, which found a resolved (B (A C)) topology. Within Heteromys, we recover 5 lineages, but the relationships among them remain unresolved. The examined South American species of Heteromys formed a clade, but 2 species recently described from Ecuador and Venezuela were not included here. Samples referred to as H. desmarestianus crassirostris and H. d. planifrons were quite distinct from other samples of H. desmarestianus, emphasizing the need for alpha-level taxonomic revision of this species complex. Given the current results, future studies can now examine relationships among species of Heteromys using samples of Liomys as outgroups, but studies of Liomys must take into account its likely paraphyletic nature.