Based on morphological similarities, Jack Garrick in 1982 grouped this species with the bignose shark (C. altimus) and the sandbar shark (C. plumbeus), while Leonard Compagno in 1988 placed it as the sister species of the grey reef shark (C. amblyrhynchos). A phylogenetic analysis based on allozyme data, published by Gavin Naylor in 1992, indicated that the Caribbean reef shark is the sister taxon to a clade formed by the Galapagos shark (C. galapagensis), dusky shark (C. obscurus), oceanic whitetip shark (C. longimanus), and the blue shark (Prionace glauca). However, more work is required to fully resolve the interrelationships within Carcharhinus.
Although still abundant at Cocos Island and other relatively pristine sites, grey reef sharks are susceptible to localized depletion due to their slow reproductive rate, specific habitat requirements, and tendency to stay within a certain area. The IUCN has assessed the grey reef shark as Near Threatened; this shark is taken by multispecies fisheries in many parts of its range and used for various products such as shark fin soup and fishmeal. Another threat is the continuing degradation of coral reefs from human development. There is evidence of substantial declines in some populations. Anderson et al. (1998) reported, in the Chagos Archipelago, grey reef shark numbers in 1996 had fallen to 14% of 1970s levels. Robbins et al. (2006) found grey reef shark populations in Great Barrier Reef fishing zones had declined by 97% compared to no-entry zones (boats are not allowed). In addition, no-take zones (boats are allowed but fishing is prohibited) had the same levels of depletion as fishing zones, illustrating the severe effect of poaching. Projections suggested the shark population would fall to 0.1% of pre-exploitation levels within 20 years without additional conservation measures. One possible avenue for conservation is ecotourism, as grey reef sharks are suitable for shark-watching ventures, and profitable diving sites now enjoy protection in many countries, such as the Maldives.