Cryptantha (Boraginaceae) is a group of approximately 200 annual and perennial species, representing two-thirds of the diversity within subtribe Cryptanthinae. The genus exhibits an amphitropic distribution, occurring in temperate and desert regions of western North and South America. Fifty samples of 45 species of Cryptantha s. l., exemplars of the related genera Amsinckia, Pectocarya, and Plagiobothrys, and four outgroup taxa were sequenced for two gene regions, the nuclear ribosomal gene, ITS, and the trnLUAA intron region of the chloroplast genome. These data were used to assess phylogenetic relationships using parsimony, maximum likelihood, and Bayesian inference methods. Cryptantha s. l. was found to be polyphyletic, with its members placed among several well-supported clades. Based on these analyses, we propose resurrection of the genera Eremocarya, Greeneocharis, Johnstonella, and Oreocarya, and recognition of a newly delimited Cryptantha s. s. The related genera Amsinckia and Pectocarya were resolved as monophyletic and most closely related to various clades within Cryptantha s. l. Plagiobothrys was resolved as polyphyletic in three clades, these clades corresponding to previously named sections or groups of sections. The Cryptanthinae is supported as monophyletic. Character trait analyses support the multiple, derived evolution of perenniality, reduction in nutlet number, nutlet heteromorphism, smooth nutlet sculpturing, heterostyly, and cleistogamy. Although sampling is incomplete, this study generally supports the hypothesis of repeated, unidirectional dispersal events, from North to South America. Genera resurrected include: Eremocarya, Greeneocharis, Johnstonella, and Oreocarya. New combinations include: Greeneocharis circumscissa var. rosulata, Greeneocharis similis, Oreocarya atwoodii, Oreocarya barnebyi, Oreocarya compacta, Oreocarya crassipes, Oreocarya creutzfeldtii, Oreocarya fulvocanescens var. nitida, Oreocarya grahamii, Oreocarya hypsophila, Oreocarya johnstonii, Oreocarya ochroleuca, Oreocarya roosiorum, Oreocarya schoolcraftii, Oreocarya semiglabra, Oreocarya shackletteana, Oreocarya sobolifera, Oreocarya subcapitata, Oreocarya suffruticosa var. arenicola, Oreocarya suffruticosa var. laxa, Oreocarya suffruticosa var. pustulosa, Oreocarya suffruticosa var. setosa, Oreocarya welshii, Johnstonella angelica, Johnstonella angustifolia, Johnstonella costata, Johnstonella diplotricha, Johnstonella echinosepala, Johnstonella fastigiata, Johnstonella grayi var. cryptochaeta, Johnstonella grayi var. grayi, Johnstonella grayi var. nesiotica, Johnstonella holoptera, Johnstonella micromeres, Johnstonella parviflora, and Johnstonella pusilla.