Early mosasaurians like dolichosaurs were small long-bodied lizards that inhabited nearshore coastal and freshwater environments; the Late Cretaceous saw the rise of large marine forms, the mosasaurids, which are the clade's best-known members.

[4] The clade is defined as all descendants of the last common ancestor of the mosasaur Mosasaurus hoffmannii and dolichosaurs Dolichosaurus, Coniasaurus, and Adriosaurus suessi.

[6] Like other ancient marine reptiles, such as those in the orders Ichthyosauria and Plesiosauria, the genera in Mosasauria are not part of the clade Dinosauria.

[7] The specific placement of Mosasauria within the Squamata has been controversial since its inception, with early debate focusing on the classification of the mosasaurs.

Within that group placement varied, from placing mosasaurs within Varanoidea or its sister taxa, or as true monitor lizards within Varanidae.

[11] Multiple subsequent studies conducted by scientists such as Lee, Caldwell, and Alessandro Palci refined this hypothesis, where in some, the Mosasauria clade was revived and repurposed.

[13] However, a 2010 study by Wiens et al. attempted to replicate Lee (2009) using a larger dataset but instead yielded results that recovered the Mosasauria as a sister clade to the monitor lizards.

Pythonomorpha was originally proposed by paleontologist Edward Drinker Cope (1869) as a reptilian order comprising mosasaurs, which he believed to be close relatives of Ophidia (snakes).

Cope wrote, "In the mosasauroids, we almost realize the fictions of snake-like dragons and sea-serpents, in which men have been ever prone to indulge.

[19] As redefined by Lee (1997), the monophyletic Pythonomorpha consists of "the most recent common ancestor of mosasauroids and snakes, and all its descendants."

If Pythonomorpha is valid, it contains not only mosasauroids but the Ophidiomorpha, which was defined as a node-based clade containing the most recent common ancestor of dolichosaurs, adriosaurs, Aphanizocnemus, and fossil and extant Ophidia and all of its descendants.

A combined morphological and molecular analysis by Reeder, et al., (2015) recovered Mosasauria and Serpentes as sisters, consistent with Pythonomorpha.

[21] A 2022 analysis found that mosasaurs were most closely related to Varanoidea, and stated that they "consider most characters previously reported as supporting the Pythonomorph Hypothesis to be problematic, because of incomplete fossil preparation, artefacts of taphonomy, limited comparisons, misinterpretations of anatomy, incomplete taxon sampling, or inadequate character formulation and/or scoring".