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.
This species is taken by commercial and artisanal longline and gillnet fisheries throughout its range. It is valued for meat, leather, liver oil and fishmeal. The Caribbean reef shark is the most common shark landed in Colombia (accounting for 39% of the longline catch by occurrence), where it is utilized for its fins, oil and jaws (sold for ornamental purposes). In Belize, this species is mainly caught as bycatch on hook-and-line intended for groupers and snappers; the fins are sold to the lucrative Asian market and the meat sold in Belize, Mexico, and Guatemala to make "panades", a tortilla-like confection. A dedicated shark fishery operated in Belize from the mid-1900s to the early 1990s, until catches of all species saw dramatic declines. The flesh of this species may contain high levels of methylmercury and other heavy metals.
Dutch ichthyologist Pieter Bleeker first described the grey reef shark in 1856 as Carcharias (Prionodon) amblyrhynchos, in the scientific journal Natuurkundig Tijdschrift voor Nederlandsch-Indië. Later authors moved this species to the genus Carcharhinus. The type specimen was a 1.5 metres (4.9 ft)-long female from the Java Sea. Other common names used for this shark around the world include black-vee whaler, bronze whaler, Fowler's whaler shark, graceful shark, graceful whaler shark, grey shark, grey whaler shark, longnose blacktail shark, school shark, and shortnose blacktail shark. Some of these names are also applied to other species.
Grey reef sharks are often curious about divers when they first enter the water and may approach quite closely, though they lose interest on repeat dives. They can become dangerous in the presence of food, and tend to be more aggressive if encountered in open water rather than on the reef. There have been several known attacks on spearfishers, possibly by mistake, when the shark struck at the speared fish close to the diver. This species will also attack if pursued or cornered, and divers should immediately retreat (slowly and always facing the shark) if it begins to perform a threat display. Photographing the display should not be attempted, as the flash from a camera is known to have incited at least one attack. Although of modest size, they are capable of inflicting significant damage: during one study of the threat display, a grey reef shark attacked the researchers' submersible multiple times, leaving tooth marks in the plastic windows and biting off one of the propellers. The shark consistently launched its attacks from a distance of 6 m (20 ft), which it was able to cover in a third of a second. As of 2008, the International Shark Attack File listed seven unprovoked and six provoked attacks (none of them fatal) attributable to this species.
Caribbean reef sharks are sometimes seen resting motionless on the sea floor or inside caves; it is the first active shark species in which such a behavior was reported. In 1975, Eugenie Clark investigated the famed "sleeping sharks" inside the caves at Isla Mujeres off the Yucatan Peninsula, and determined that the sharks were not actually asleep as their eyes would follow divers. Clark speculated that freshwater upwellings inside the caves might loosen parasites on the sharks and produce an enjoyable "narcotic" effect. If threatened, Caribbean reef sharks sometimes perform a threat display, in which they swim in a short, jerky fashion with frequent changes in direction and repeated, brief (1–1.2 second duration) drops of the pectoral fins. This display is less pronounced than the better-known display of the grey reef shark (C. amblyrhynchos).
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.