Analyzing circulating cell free DNA (ccfDNA) offers a non-invasive, dynamic window into the body’s physiological state and its use as a biomarker is gaining rapidly. However, multiple challenges remain with establishing its routine application. This is mainly due to its low levels, high rates of fragmentation, and preanalytical variabilities associated with sample collection, cfDNA extraction and quantification. Here, we go through some tips on how one can establish a reliable cfDNA workflow from plasma samples.