Upper Cretaceous marine rocks of the Big Bend Region of trans-Pecos Texas preserve a number of marine-adapted mosasauroids. At least three unnamed taxa of basal mosasauroids are represented by remains from shaly limestones in the middle Turonian portion of the Boquillas Formation. These occur along with remains of larger derived mosasaurs referable to Russellosaurina and an undescribed tylosaurine. Derived mosasaurs from the middle to late Coniacian include the first report of Tylosaurus kansasensis outside of Kansas, T. nepaeolicus, Platecarpus planifrons, and Platecarpus aff. P. planifrons. Clidastes liodontus is found in the latest Coniacian or early Santonian part of the Pen Formation. An undescribed species of Ectenosaurus, Clidastes sp. and an indeterminate plioplatecarpine occurs in the middle Santonian to early Campanian interval of the Pen Formation. The mosasaur fauna from the Big Bend region is quite similar to that from the Smoky Hill Chalk of Kansas, a thousand kilometres to the north. We refine the position of the Cenomanian–Turonian boundary within the Ernst Member of the Boquillas Formation, based on ammonite faunas. We also corroborate previous interpretations describing the time-transgressive nature of the onset of deposition of the Pen Formation based on a west-to-east descending level of the Inoceramus (Cremnoceramus) undulatoplicatus FAD.