A fundamental goal of surgical pathology is to distinguish benign lesions from malignant ones [74, 75]. It is also equally important to be able to differentiate between indolent and aggressive tumors . The use of hematoxylin and eosin (H&E) staining as well as the use of various special stains; backed with good clinicopathologic acumen, has partly improved the diagnosis of disease, albeit this is sometimes with limited diagnostic accuracy [77, 78]. The introduction of immunohistochemistry into diagnostic pathology significantly improved the confirmation of diagnoses, where morphological differential diagnosis using H&E presented a dilemma. However, immunohistochemistry has been cautiously used and interpreted after its limitations (such as variable antibody reactivity, background staining, poor quantitation, and subjective interpretation) became apparent [78–85]. Another layer of complexity is added to the diagnostic dilemma by intratumour heterogeneity and inter-biopsy heterogeneity, which presupposes that multiple cancer molecular signals can be detected in various sampled regions [86, 87]. This alludes to the notion that molecular classification of disease may be complimentary and in some situations more important than conventional histopathological diagnosis based on H&E staining [88–92]. The advent of various omics based molecular approaches as described hereafter, can potentially improve the diagnosis and monitoring of disease, particularly in the diagnostic grey areas. The benefit of using multiple high throughput techniques in a complementary and integrated manner would no doubt benefit personalized/precision medicine and the field of diagnostic oral pathology immensely (Fig. 1).Fig. 1Impact of omics based molecular approaches on personalized/precision medicine and the field of diagnostic oral pathology