In both research and clinical settings, liquid biopsies using cell-free circulating tumor DNA ( ctDNA ) are frequently used. In order to tailor systemic therapy, find post-treatment minimal residual disease ( MRD ), and predict immunotherapy responses, ctDNA can be used to identify actionable mutations. Additionally, ctDNA can be isolated from a variety of biofluids, and if sampling more closely than blood plasma, it may be possible to detect locoregional MRD with higher sensitivity. In early-stage and post-treatment MRD settings, where ctDNA levels are low and pose a high risk for false negative results, which is balanced with the risk of false positive results from clonal hematopoiesis, it is still difficult to detect the disease. In order to overcome these difficulties, researchers have created ever-more sophisticated methods to increase assay sensitivity and specificity by reducing sources of low-level technical and biological noise and by harnessing particular genomic and epigenomic features of ctDNA. These methods aim to reduce the limit of detection( LOD ) of the – per-million range. In this review, we highlight a variety of contemporary ctDNA analysis assays, including improvements to the signal-to-noise ratio. We also draw attention to the difficulty of identifying ultra-rare tumor-associated variants, which will increase the sensitivity of post-treatment MRD detection and pave the way for the development of personalized adjuvant treatment decisions.