Solanum, with approximately 1,500 species, is the largest genus in the Solanaceae and includes economically important species such as the tomato, potato, and eggplant. In part due to its large size and tropical center of diversity, resolving evolutionary relationships across Solanum as a whole has been challenging. In order to identify major clades within Solanum and to gain insight into phylogenetic relationships among these clades, we sampled 102 Solanum species and seven outgroup taxa for three DNA sequence regions (chloroplast ndhF and trnT-F, and nuclear waxy) and analyzed the data using parsimony and Bayesian methods. The same major Solanum clades were identified by each data partition, and the combined analysis provided the best resolved hypothesis of relationships within the genus. Our data suggest that most traditionally recognized Solanum subgenera are not monophyletic. The Thelopodium clade is sister to the rest of Solanum, which is split into two large clades. These two large clades are further divided into at least 10 subclades, for which informal names are provided and morphological synapomorphies are proposed. The identification of these subclades provides a framework for directed sampling in further phylogenetic studies, and identifies natural groups for focused revisionary work.