The Gulf of Guinea is a marine biodiversity hotspot, but cetacean fauna in these waters is poorly studied and our knowledge is documented mostly from opportunistic (sightings and strandings) and whaling data. This chapter presents a short review of historical whaling in the Gulf of Guinea and an update of cetacean biodiversity in the waters of São Tomé and Príncipe. Observations since 2002 have confirmed the presence of 12 species of cetaceans, 5 of them new to the region (Striped Dolphin, Rough-toothed Dolphin, Risso’s Dolphin, Pygmy Killer Whale, and Dwarf Sperm Whale). The archipelago seems to be an important area for cetaceans, with some species (Bottlenose Dolphin and Pantropical Spotted Dolphin) being present throughout the year. The volcanic origin of the archipelago produces great depths very close to the coast, which may favor the approach of pelagic species like Sperm Whales, Killer Whales, and Short-finned Pilot Whales. Bays and shallow waters may also serve as protection or rest areas for particular groups, like mother and calf pairs of Humpback Whales. Major anthropogenic threats to cetaceans in São Tomé and Príncipe include habitat degradation due to overfishing, fisheries interactions, possibly some occasionally directed takes and, more recently, oil and gas prospecting. Consistent and dedicated research to inform national legislation, together with increasing environmental awareness and local engagement, would help to identify effective cetacean conservation strategies in the archipelago.