With recent fossil discoveries, South African Plio-Pleistocene hominin diversity is increasing, with the inferred (co)existence of a number of species representing the three genera Australopithecus, Paranthropus and Homo [1]. In particular, two to three Australopithecus species are recognized: Au. africanus, Au. sediba and possibly Au. prometheus. Paranthropus is predominantly represented by the endemic species P. robustus, with the GDA-2 molar from Gondolin also exhibiting morphology similar to eastern African P. boisei [2]. Regarding Homo, three Early Pleistocene species have been proposed, including H. habilis, H. erectus/ergaster, H. gautengensis, and one Middle Pleistocene taxon, H. naledi, was recently described [1,3]. It is also noteworthy that the South African fossil hominin record is mainly represented by dentognathic remains. In mammal paleobiology, tooth morphology is considered a highly reliable element for taxonomic assessment. However, the original shape of the outer crown is often altered by occlusal wear and/or taphonomic processes. For this reason, the taxonomic allocation of some hominin dentognathic remains is still controversial, even at the genus level. This is the case for a number of specimens from the cave deposits of Kromdraai (e.g., KB 5223), Swartkrans (e.g., SK 15, SK 27, SK 45, SKX 257-258) and Sterkfontein (e.g., StW 53, StW 80, StW 151), which are often attributed to different Homo species, or even sometimes regarded as representing Australopithecus or Paranthropus [1,4]. Such uncertainty affects the reconstruction of reliable taxon-specific evolutionary trajectories which, in turn, should rely upon solid taxonomic hypotheses. We used non-invasive X-ray microtomographic imaging to characterize the molar structural signature of this controversial fossil assemblage. We then compared these results with the endostructural features displayed by a number of extant and fossil hominins, including East African H. erectus/ergaster from Mulhuli-Amo, North African late Early Pleistocene Homo from Tighenif, and Indonesian H. erectus s.s. from Sangiran. In addition, these comparisons were made with samples representing Au. africanus and P. robustus, including their respective holotypes (i.e., Taung and TM 1517). Besides the virtual exploration and deformation-based geometric morphometric (GM) analysis of the enamel-dentine junction (EDJ) and root system, we also assessed the crown tissue proportions (through the 3D relative enamel thickness index) and the enamel thickness distribution pattern (rendered by chromatic scale cartographies). By combining quantitative information from the molar and root structural organization, our results unambiguously confirm the attribution of SK 27 to the genus Homo, more likely related to H. ergaster/erectus. The specimen StW 80 shows an intermediate signal between the australopiths and Homo. All the other specimens purportedly regarded as Homo, even if displaying some Homo-like features (more gracile morphology, thick but not hyper-thick enamel), align either with Paranthropus or Australopithecus. In particular, the GM analyses of the EDJ of KB 5223, SK 15, and SKX 257-258 clearly distinguishes them from Homo and place them close to or inside the variability of Paranthropus. In addition, these analyses discriminate StW 151 from Homo and place it inside the Australopithecus range. Until more precise information on their original chrono-stratigraphic context is available, similar analyses including other Early-Middle Pleistocene South African hominin taxa, like Au. sediba and H. naledi, could shed light on local hominin paleobiodiversity.