Although current classifications in surgical pathology for identifying and staging malignancies are largely based on anatomic features (e.g., tumor-node-metastasis staging) and histopathology (e.g., tumor grade/ frequency), advances in the genome sciences are increasingly providing reliable genetic markers for diagnosing cancer and setting treatment regimens. For example, microarrays together with clustering algorithms are revealing a molecular diversity among cancers that promises to form a new taxonomy with prognostic and therapeutic significance. A future challenge to realizing more personalized cancer therapy will therefore be the development and implementation of robust cost-effective technologies to assay clinical specimens against these panels of molecular markers. The diversity of genomic alterations (mutations, deletions, insertions, translocations, copy number variations, etc.) involved in malignancy necessitates a variety of assays for accurate cancer profiling. In this seminar, I will report on our efforts to develop and commercialize a new platform technology for detecting and quantifying cancer biomarkers at the level of a rare allele bearing a somatic point mutation within a blood or dense tissue specimen containing the associated wild-type allele in high abundance, or a mutational hotspot within a defined sequence of connected codons known to be a driver of cancer pathogenesis, all the way up to the level of complex reciprocal translocation of large amounts of chromosomal material. The platform exploits advances in PCR technology, most notably digital PCR formats, as well as non-natural nucleotide chemistries that are specifically designed to improve detection limits and analytical specificities, allowing, for example, the detection of one copy of a mutant allele bearing a single cancer-driving somatic point mutation within a background of a million or more copies of the associated wild-type gene. The unique chemistries and thermodynamic properties of these modified oligonucleotides will be presented, along with a molecular thermodynamic model that is integral to assay design. Examples of the use of assays developed using the platform in hospitals and cancer genetics testing laboratories will be provided.