The sunflower genus, Helianthus, is recognized widely for the cultivated sunflower H. annuus and scientifically as a model organism for studying diploid and polyploid hybrid speciation, introgression, and genetic architecture. A resolved phylogeny for the genus is essential for the advancement of these scientific areas. In the past, phylogenetic relationships of the perennial species and polyploid hybrids have been particularly difficult to resolve. Using the external transcribed spacer region of the nuclear 18S-26S rDNA region, we reveal for the first time a highly resolved gene tree for Helianthus. Phylogenetic analysis allowed the determination of a monophyletic annual H. sect. Helianthus, a two-lineage polyphyletic H. sect. Ciliares, and the monotypic H. sect. Agrestis, all of which were nested within a large perennial and polyphyletic H. sect. Divaricati. The distribution of perennial polyploids and known annual diploid hybrids on this phylogeny suggested multiple independent hybrid speciation events that gave rise to at least four polyploids and three diploid hybrids. Also provided by this phylogeny was evidence for homoploid hybrid speciation outside H. sect. Helianthus. Finally, previous hypotheses about the secondary chemistry in the genus were tested in a phylogenetic framework to obtain a better understanding of the evolution of these compounds in Helianthus.