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Senecioneae is the largest tribe of Asteraceae, comprised of ca. 150 genera and 3,000 species. Approximately one‐third of its species are placed in Senecio , making it one of the largest genera of flowering plants. Despite considerable efforts to classify and understand the striking morphological diversity in Senecioneae, little is known about its intergeneric relationships. This lack of phylogenetic understanding is predominantly caused by conflicting clues from morphological characters, the large size of the tribe, and the absence of a good delimitation of Senecio . Phylogenetic analyses of nrITS and plastid DNA sequence data were used to produce a hypothesis of evolutionary relationships in Senecioneae and a new, monophyletic, delimitation of Senecio . The results of separate and combined phylogenetic analyses of the two datasets were compared to previous taxonomic treatments, morphological and karyological data, and biogeographic patterns. These studies indicate that the subtribal delimitation of Senecioneae needs to be revised to reflect exclusively monophyletic subtribes. This would involve abolishing subtribes Adenostylinae, Blennospermatinae, and Tephroseridinae and recognizing subtribes Abrotanellinae, Othonninae, and Senecioninae. Moreover, Tussilagininae may need to be split into three or four subtribes: Brachyglottidinae, Chersodominae, Tussilagininae, and perhaps Doronicinae. On the intergeneric level, these phylogenies provide new insights into evolutionary relationships, resulting in a first approximation of a comprehensive phylogeny for the tribe. Most species currently assigned to Senecio form a well supported clade. Thus, a new delimitation of Senecio is proposed, which involves transferring the species of Aetheolaena, Culcitium, Hasteola, Iocenes, Lasiocephalus , and Robinsonia to Senecio and removing several Senecio groups that are only distantly related to the core of Senecio . Area optimization analyses indicate a strong African influence throughout the evolutionary history of Senecioneae, predominantly in subtribes Senecioninae and Othonninae.