Liquid biopsy in its current form is dependent on circulating cell-free DNA (cfDNA) analysis; this method likewise presents multiple challenges. These include variations in DNA shedding between tumors as well as low sensitivity (especially in early-stage cancer), difficulty in detecting fusion genes (i.e., chromosomal translocations leading to the expression of chimeric mRNA from two genes), and inability to reflect the numerous biological processes that modify RNA expression levels, such as alternative splicing, stability, and allele-specific methylation. The latter limitation is critically important as recent studies have shown that RNA testing provides another level of biological information regarding the tumor and its microenvironment.