Simple SummaryMouth cancer often results in poor outcomes and requires the use of state-of-the-art medical approaches to make its detection easy, individualized, and early. Liquid biopsy is a new and important medical approach to disease detection. This approach has been successfully used for mouth cancer detection and monitoring of treatment progress in many countries. Liquid biopsy is an attractive option for mouth cancer detection because it does not involve any invasive procedure and can be used on easily accessible body fluids, such as saliva and blood. Furthermore, there is evidence that this technology has some advantage over the normal tissue biopsy because it is not invasive, neither does it need any surgical expertise. Hence, we have focused on how easy or practical it would be, to employ the use of liquid biopsy on the African continent, as well as other low- and middle-income countries. We have discussed the different types of this technology in three main areas of focus, viz, what factors are important before, during and after collection of samples for liquid biopsy analysis, and what are the obstacles to routine use of this approach in resource-limited settings.An important driving force for precision and individualized medicine is the provision of tailor-made care for patients on an individual basis, in accordance with best evidence practice. Liquid biopsy(LB) has emerged as a critical tool for the early diagnosis of cancer and for treatment monitoring, but its clinical utility for oral squamous cell carcinoma (OSCC) requires more research and validation. Hence, in this review, we have discussed the current applications of LB and the practicality of its routine use in Africa; the potential advantages of LB over the conventional “gold-standard” of tissue biopsy; and finally, practical considerations were discussed in three parts: pre-analytic, analytic processing, and the statistical quality and postprocessing phases. Although it is imperative to establish clinically validated and standardized working guidelines for various aspects of LB sample collection, processing, and analysis for optimal and reliable use, manpower and technological infrastructures may also be an important factor to consider for the routine clinical application of LB for OSCC. LB is poised as a non-invasive precision tool for personalized oral cancer medicine, particularly for OSCC in Africa, when fully embraced. The promising application of different LB approaches using various downstream analyses such as released circulating tumor cells (CTCs), cell free DNA (cfDNA), microRNA (miRNA), messenger RNA (mRNA), and salivary exosomes were discussed. A better understanding of the diagnostic and therapeutic biomarkers of OSCC, using LB applications, would significantly reduce the cost, provide an opportunity for prompt detection and early treatment, and a method to adequately monitor the effectiveness of the therapy for OSCC, which typically presents with ominous prognosis.