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.
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Grey reef sharks are prey for larger sharks, such as the silvertip shark. At Rangiroa Atoll in French Polynesia, great hammerheads (Sphyrna mokarran) feed opportunistically on grey reef sharks that are exhausted from pursuing mates. Known parasites of this species include the nematode Huffmanela lata and several copepod species that attach to the sharks' skin, and juvenile stages of the isopods Gnathia trimaculata and G. grandilaris that attach to the gill filaments and septa (the dividers between each gill).
Ancient reefs buried within stratigraphic sections are of considerable interest to geologists because they provide paleo-environmental information about the location in Earth's history. In addition, reef structures within a sequence of sedimentary rocks provide a discontinuity which may serve as a trap or conduit for fossil fuels or mineralizing fluids to form petroleum or ore deposits.