Early detection of diseases such as cancer can drastically improve long term survival rates and lower healthcare costs, but currently frequent diagnosis is not easy, practical, or economical for potential patients. Circulated nucleic acid molecules can serve as signatures for a wide range of diseases, and thus possess great potential as biomarkers for a "liquid biopsy." However, a 50-microliter drop of blood contains approximately 10 quintillion nucleotides, and finding one 25-nucleotide signature molecule is a needle-in-a-haystack problem of epic proportions. Today, I will talk about how DNA molecular engineering enables ultra-specific and highly sensitive nucleic acid probes and sensors, and how these molecular scale tools can be integrated with label-free optical readout devices for economical assays. The eventual goal is to build a handheld device (like the glucose-meter) that enables frequent testing for a variety of diseases in a point-of-care or primary care setting.