A major goal of molecular diagnostics is to find a sensitive and specific means for detecting and quantifying DNA fragments from rare cancer cells (by virtue of an identifying somatic mutation) in a clinical sample containing DNA fragments from abundant normal cells. Such a sensitive technique would enable "liquid biopsies" of the DNA fragments released into blood plasma as a consequence of apoptosis and necrosis (irrespective of the location of the tumor), enabling an early determination of prognosis, propensity to metastasize, and sensitivity to different therapies, for each individual patient. The approach taken by our laboratory towards meeting this challenge is to design oligonucleotide primers for polymerase chain reaction (PCR) assays that are extraordinarily selective, initiating amplification on (mutant) sequences that are perfectly complementary to the primer, while virtually ignoring (wild-type) sequences that mismatch the primer sequence by a single-nucleotide difference.