Based on extensive molecular and morphological data, all of the native South American species previously assigned to Sisymbrium (tribe Sisymbrieae) are assigned to the genera Chilocardamum, Mostacillastrum, Neuontobotrys, and Polypsecadium of the tribe Schizopetaleae (Brassicaceae). Akey distinguishing these four genera is presented. For each genus, a revised synopsis, an expanded generic description, a key to species, and an enumeration of all taxa is given. Polypsecadium zoellneri is described as a new species from northern Chile, and its distinguishing characters from its nearest relative P. gilliesii are discussed. The following 36 new combinations are proposed: Chilocardamum castellanosii, C. longistylum, C. onuridifolium, Mostacillastrum andinum, M. carolinense, M. commune, M. dianthoides, M. ferreyrae, M. gracile, M. leptocarpum, M. morrisonii, M. oleraceum, M. orbignyanum, M. pectinifolium, M. sagittatum, M. subscandens, M. ventanense, M. weberbaueri, Neuontobotrys choiquense, N. frutescens, N. grayana, N. lanata, N. mendocina, N. polyphylla, N. tarapacana, Polypsecadium adscendens, P. arnottianum, P. brasiliense, P. effusum, P. gilliesii, P. litorale, P. llatasii, P. magellanicum, P. rusbyi, P. solidagineum, and P. tucumanense.