Gene mutation is associated with cancer and the dissemination of circulating biomarkers through the blood represents a vital transitional step that exemplifies the shift from localized to systemic disease. The detection and characterization of circulating tumor biomarkers at an early stage is therefore essential as a conventional approach to monitor and suppress the initiation of overt metastatic disease. Currently, the genetic profiles of solid tumors are obtained from needle biopsies, which provides a glimpse of tumor heterogeneity. Furthermore, some tumor entities such as lung cancer are situated at remote sites and a needle biopsy can be very difficult and can increase chances of tumor seeding. Thus, the analysis of circulating tumor cells (CTCs) and cell-free circulating nucleic acids (in particular circulating tumor DNA-ctDNA) and tumor derived exosomes released into the peripheral blood from the primary tumor and/or metastatic deposits by minimally invasive means, can provide the full genetic landscape of all cancerous lesions, and can enable systematic tracking of genomic evolution. Herein, we explore how circulating biomarkers (CBs) detectable in bodily fluids can be utilized for diagnosis, prognosis evaluation and prediction of response to treatments. We also discuss the current and emerging methods for analysing CBs as well as biological and technical challenges. Deficiencies of detection methods are identified, with subsequent critical overview of methods to address them.