Cuphea is an endemic genus of the New World and the most speciose member of the Lythraceae with ca. 260 species classified in two subgenera and 13 sections. As a first attempt to construct a phylogenetic framework for the genus, data from morphology and nuclear ITS sequences for 53 species and four outgroup taxa were analyzed. Independent results employing morphological and molecular datasets confirmed Cuphea as monophyletic with Pleurophora as sister. The morphological strict consensus tree was substantially unresolved. The ITS parsimony and maximum likelihood phylogenies indicated South America as the initial center of diversification and identified a deep trichotomy, one branch of which was equivalent to subg. Cuphea. The ITS analyses also recognized seven well-supported clades, each composed of members from two to four taxonomic sections. Species of section Melvilla appear in five of the seven clades, supporting the hypothesis that the large, intensely-colored, bird-pollinated floral tubes that define the section are convergent, having evolved from smaller, more promiscuously-pollinated, green-tubed flowers. Sixteen endemic North American species have a single South American origin and form the core of a secondary center of Cuphea diversification in Mexico. The ITS analyses provide initial phylogenetic hypotheses for the genus that clarify relationships previously obscured by the highly homoplastic nature of the morphological taxonomic characters.