The species of the cosmopolitan sponge genus Mycale occurring in the tropical Indo-West Pacific region and adjacent subtropical waters are reviewed taxonomically. Specimens incorporated in the collections of the Naturalis Biodiversity Center form the basis of this comprehensive study, supplemented by (type) specimens borrowed from or examined in other institutions. Specimens available numbered 351, belonging to 44 species, including 14 species new to science, Mycale (Aegogropila) prognatha sp.nov., Mycale (Carmia) amiri sp.nov., Mycale (Carmia) fungiaphila sp.nov., Mycale (Carmia) monomicrosclera sp.nov., Mycale (Carmia) tenuichela sp.nov., Mycale (Carmia) tubiporicola sp.nov., Mycale (Carmia) tydemani sp.nov., Mycale (Mycale) asigmata sp.nov., Mycale (Mycale) grandoides sp.nov., Mycale (Mycale) sundaminorensis sp.nov., Mycale (Naviculina) mascarenensis sp.nov., Mycale (Paresperella) sceptroides sp.nov., Mycale (Paresperella) seychellensis sp.nov., Mycale (Zygomycale) sibogae sp.nov. Three species, indicated by the designation ‘aff.’, were not definitely assigned to known or new species due to uncertainty of their identity. The genus Kerasemna, previously considered a junior synonym of Mycale, was revived as an additional subgenus Mycale (Kerasemna). One species, previously assigned to the genus Desmacella as D. lampra De Laubenfels is here reassigned to Mycale, subgenus at present undecided. Additionally, species previously reported from the region but not represented in our collections are briefly characterized and discussed. We propose new names Mycale (Mycale) mauricei nom.nov. for Mycale macrochela Burton (junior primary homonym of Mycale fistulata var. macrochela Hentschel) and Mycale (Mycale) bouryesnaultae nom.nov. for Mycale (Mycale) fibrosa Boury-Esnault & Van Beveren (junior primary homonym of Mycale (Aegogropila) adhaerens subsp. fibrosa Koltun). Keys to the species of each subgenus occurring in the region are provided. The opportunity of having studied this comprehensive set of species and specimens from the tropical Indo-West Pacific is taken to review and discuss the morphological and biogeographical data gathered so far on the genus Mycale. The genus currently comprises approximately 255 accepted species, with highest diversity focused in tropical Atlantic and Indo-West Pacific regions as well as in warm-temperate Mediterranean-Atlantic regions.