Lithospermum L. (Boraginaceae) includes approximately 60 species of which 43 occur in Mexico, with 32 endemic to the country. Through morphological and molecular investigations, the species of the genus are taxonomically revised. A broad generic circumscription is recognized and includes species traditionally recognized as members of Lithospermum as well as other New World Lithospermeae. Three new species are described from northern Mexico—Lithospermum chihuahuanum J. I. Cohen, Lithospermum kelloggianum J. I. Cohen, and Lithospermum tenerum J. I. Cohen—and each is known from only its type specimen. Lasiarrhenum confundum B. L. Turner is transferred to Lithospermum confundum (B. L. Turner) J. I. Cohen on the basis of flowers similar to those of Lithospermum trinervium (Lehm.) J. I. Cohen. The type for Pentalophus A. DC. is designated. Lectotypes are designated for Lithospermum albicans Greene [= Lithospermum incisum Lehm.], Lithospermum approximatum Brand [= Lithospermum distichum Ortega], Lithospermum breviflorum Engelm. & A. Gray [= Lithospermum incisum Lehm.], Lithospermum cobrense Greene, Lithospermum cognatum Greene ex Spengle [= Lithospermum multiflorum Torr. ex A. Gray], Lithospermum euryphyllum Brand [= Lithospermum oblongifolium Greenm.], Lithospermum galeottii Brand [= Lithospermum calycosum (J. F. Macbr.) I. M. Johnst.], Lithospermum gentianoides Brand [= Lithospermum obovatum J. F. Macbr.], Lithospermum hoyasense Brand [= Lithospermum calcicola B. L. Rob.], Lithospermum laevigatum Sessé & Moc. [= Lithospermum distichum Ortega], Lithospermum madrense Brand [= Lithospermum calcicola B. L. Rob.], Lithospermum matamorense DC., Lithospermum nelsonii Greenm., Lithospermum obtusiflorum Sessé & Moc. [= Lithospermum discolor M. Martens & Galeotti], Lithospermum sordidum Brand [= Lithospermum distichum Ortega], and Lithospermum spathulatum M. Martens & Galeotti [= Lithospermum distichum Ortega]. Lithospermum viride Greene is neotypified.