Based on separately obtained and analyzed molecular data and within the framework of a global revision of the family Trypetheliaceae, 21 new species are described, from the Neotropics and tropical Asia, in the genera Architrypethelium (1), Astrothelium (15), Bathelium (1), Nigrovothelium (1), Trypethelium (1), and Viridothelium (2), namely: Architrypethelium lauropaluanum Lücking, M. P. Nelsen & Marcelli sp. nov., differing from A. hyalinum in the perithecia immersed between coarse thallus verrucae and in the additional ascospore septa; Astrothelium aurantiacocinereum Lücking, Naksuwankul & Lumbsch sp. nov., differing from A. aeneum in the prominent, well-delimited, trypethelioid pseudostromata and the absence of pigment on the thallus surface, as well as in the barely lichenized thallus; A. carassense Lücking, M. P. Nelsen & Marcelli sp. nov., differing from A. purpurascens in orange, K+ red pseudostroma pigment and the slightly larger ascospores; A. cryptolucens Lücking, M. P. Nelsen & N. Salazar sp. nov., differing from A. carrascoense in the inspersed hymenium; A. fijiense Lücking, Naksuwankul & Lumbsch sp. nov., differing from A. cinereorosellum in the presence of lichexanthone on the well-delimited pseudostromata and in the slightly shorter ascospores; A. laevithallinum Lücking, M. P. Nelsen & Marcelli sp. nov., differing from A. endochryseum in the smooth thallus; A. leucosessile Lücking, M. P. Nelsen & Aptroot sp. nov., differing from A. phlyctaena in the conspicuous, sessile pseudostromata; A. macrostomoides Lücking, M. P. Nelsen & Benatti sp. nov., differing from A. macrostomum in the larger ascospores; A. megacrypticum Lücking, M. P. Nelsen & N. Salazar sp. nov., differing from A. longisporum in the single-spored asci and larger ascospores; A. nicaraguense Lücking, M. P. Nelsen & T. Orozco sp. nov., differing from A. gigantosporum in the smaller ascospores; A. norisianum Lücking, M. P. Nelsen & Aptroot sp. nov., differing from A. sepultum in the distinct, well-delimited pseudostromata; A. obtectum Lücking, M. P. Nelsen & Benatti sp. nov., differing from A. nigrocacuminum in the smaller ascospores; A. sordithecium Lücking, M. P. Nelsen & Marcelli sp. nov., differing from A. leucothelium in the inspersed hymenium and the absence of lichexanthone from the thallus surface outside the pseudostromata; A. subendochryseum Lücking, M. P. Nelsen & Marcelli sp. nov., differing from A. endochryseum in the absence of pigment in the pseudostromata and the lateral thallus cover of the pseudostromata; A. subinterjectum Lücking, M. P. Nelsen & Jungbluth sp. nov., differing from A. obtectum in the smaller pseudostromata and smaller ascospores, and from A. interjectum in the diffuse pseudostromata and smaller ascospores; Bathelium porinosporum Lücking, M. P. Nelsen & Gueidan sp. nov., differing from other Bathelium species in the 3-septate, euseptate ascospores; Nigrovothelium bullatum Lücking, Upreti & Lumbsch sp. nov., differing from N. tropicum in the bullate thallus; Trypethelium tolimense Lücking, Moncada & M. Gut. sp. nov., differing from T. xanthoplatystomum in the absence of a yellow-orange pigment on the pseudostromata and the K+ yellow (not K+ red) medullary pigment; Viridothelium tricolor Lücking, M. P. Nelsen & N. Salazar sp. nov., characterized by black perithecia with a lateral ostiole immersed in white pseudostromata strongly contrasting with the surrounding brown thallus, in combination with 2-spored asci and large, muriform ascospores; and V. vonkonratii Lücking, Naksuwankul & Lumbsch sp. nov., differing from V. virens in larger ascospores and mostly solitary ascomata. All species are illustrated and their taxonomy and phylogenetic relationships are discussed. ITS barcoding sequences are reported for five specimens of Bathelium porinosporum.