The shell microstructure of Carboniferous and Triassic permophorids; Triassic and Recent carditids; Devonian, Carboniferous, and Triassic crassatelloideans; and Jurassic through Recent cardioideans is examined in a phylogenetic context, using separate microstructural and morphologic data sets, as well as a combined data set. The microstructural and morphologic data sets are significantly incongruent, but the combined data set suggests that modiomorphoideans (modiomorphids and permophorids) are basal to crassatelloideans; crassatelloideans are basal to carditids (including Septocardia), and carditids are basal to cardiids. On the other hand, the possibility of direct permophorid ancestry for the carditid-cardiid clade cannot be excluded, as suggested by the retention of permophorid-like matted (transitional nacreous-porcelaneous) structure in some early carditids and cardiids. In the absence of stratigraphic data and other evidence for phylogenetic relationships, shell microstructure offers limited potential for assessing subfamily-level phylogenetic relationships within the Cardioidea. This is because of microstructural convergences reflecting biomechanical adaptations for fracture control and abrasion resistance, and possibly also selection for metabolic economy of secretion in tropical, oligotrophic habitats. General evolutionary trends in cardiid shell microstructure are nevertheless apparent: Cretaceous cardiids completely replaced an ancestral laminar, matted structure in their inner shell layer with non-laminar porcelaneous structures; evolved better defined CL structure, stronger reflection of the shell margins, and increased thickness or secondary loss of the ancestral prismatic outer shell layer; and, in Protocardia (Pachycardium) stantoni, added inductural deposition. Some Cenozoic cardiids then evolved wider first-order crossed lamellae, non-denticular composite prisms, composite fibrous prisms, ontogenetic submergence of a juvenile non-denticular composite prismatic outer shell layer into the CL middle shell layer, or ontogenetic submergence of the inner part of a juvenile fibrous prismatic outer shell layer into the CL middle shell layer.

The shell microstructure of Hemidonax donaciformis is unusual for a cardioidean, and suggests closer affinities with the superfamily Tellinoidea than with the superfamily Cardioidea.

Extensive inductural deposits in Protocardia (Pachycardium) stantoni raise the possibility that photosymbiosis evolved among some Mesozoic members of the Protocardiinae, thereby increasing the likelihood that this feature has evolved several times independently in the Cardiidae.

Cemented, calcareous periostracal granules or spines are known to occur in modiolopsoideans, mytiloideans, modiomorphids, permophorids, trigonioids, astartids, cardiids, myoids, pholadomyoids, and septibranchoids. Consequently, the presence of these structures is not necessarily indicative of close anomalodesmatan affinities.