The molecular landscape of tumors has been traditionally established using a biopsy or resection specimens. These modalities result in sampling bias that offer only a single snapshot of tumor heterogeneity. Over the last decade intensive research towards alleviating such a bias and obtaining an integral yet accurate portrait of the tumors, evolved to the use of established molecular and genetic analysis using blood and several other body fluids, such as urine, saliva, and pleural effusions as liquid biopsies. Genomic profiling of the circulating markers including circulating cell-free tumor DNA (ctDNA), circulating tumor cells (CTCs) or even RNA, proteins, and lipids constituting exosomes, have facilitated the diligent monitoring of response to treatment, allowed one to follow the emergence of drug resistance, and enumerate minimal residual disease. The prevalence of tumor educated platelets (TEPs) and our understanding of how tumor cells influence platelets are beginning to unearth TEPs as a potentially dynamic component of liquid biopsies. Here, we review the biology, methodology, approaches, and clinical applications of biomarkers used to assess liquid biopsies. The current review addresses recent technological advances and different forms of liquid biopsy along with upcoming challenges and how they can be integrated to get the best possible tumor-derived genetic information that can be leveraged to more precise therapies for patient as liquid biopsies become increasingly routine in clinical practice.