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Early diagnosis of cancer improves the efficacy of curative therapies. However, due to the difficulties involved in distinguishing between small early-stage tumors and normal biological variation, early detection of cancer is an extremely challenging task and there are currently no clinically validated biomarkers for a pan-cancer screening test. It is thus of particular significance that increasing evidence indicates the potential of circulating tumor DNA (ctDNA) molecules, which are fragmented segments of DNA shed from tumor cells into adjacent body fluids and the circulatory system, to serve as molecular markers for early cancer detection and thereby allow early intervention and improvement of therapeutic and survival outcomes. This is possible because ctDNA molecules bear cancer-specific fragmentation patterns, nucleosome depletion motifs, and genetic and epigenetic alterations, as distinct from plasma DNA originating from non-cancerous tissues/cells. Compared to traditional biomarkers, ctDNA analysis therefore presents the distinctive advantage of detecting tumor-specific alterations. However, based on a thorough survey of the literature, theoretical and empirical evidence suggests that current ctDNA analysis strategies, which are mainly based on DNA mutation detection, do not demonstrate the necessary diagnostic sensitivity and specificity that is required for broad clinical implementation in a screening context. Therefore, in this review we explain the biological, physiological, and analytical challenges toward the development of clinically meaningful ctDNA tests. In addition, we explore some approaches that can be implemented in order to increase the sensitivity and specificity of ctDNA assays. [ABSTRACT FROM AUTHOR]