Defined by the updip limit of the first basin-wide depositional unit, the Louann Salt, the Gulf of Mexico sedimentary basin extends from the southern US coastal plain to southern Mexico, Chiapas and Tabasco regions, and east across Yucatán to Cuba, the Florida Straits, and onshore Florida. The unique structural setting of salt and extensional tectonics (and Neogene Mexico compressional events) controls how the Mesozoic and Cenozoic depositional history evolves. This is illustrated by basin-scale cross-sections across the USA, Mexico, and Cuba, onshore to offshore. The 200-million-year depositional history is viewed through a six-stage tectonostratigraphic framework reflecting hinterland source terrane uplift, sediment routing, basin accommodation, and sea-level change. Stratigraphic terminology for Mesozoic and Cenozoic strata and depositional systems classifications for ancient carbonates and siliciclastics are explained, facilitating detailed unit descriptions. The database of seismic reflection interpretations, biostratigraphy, well logs, provenance analysis, carbonate reef, and siliciclastic shelf margin and deepwater system mapping that underpins the paleogeographic maps is detailed.