Approximately one in three adults in the United States sleeps less than the recommended 7 h per night. Decades of epidemiological data and data from experimental sleep restriction studies demonstrate short sleep duration is associated with adverse cardiometabolic risk, including risk of type 2 diabetes and cardiovascular disease. However, the precise mechanisms underlying this risk are not fully elucidated and there is a lack of sleep-based interventions designed to mitigate such risk. One strategy to overcome these limitations is to develop biomarkers that link habitual short sleep duration with adverse cardiometabolic risk. Such biomarkers could inform biochemical mechanisms, identify new targets for interventions, support precision medicine by identifying individuals most likely to benefit from sleep-based interventions, and ultimately lead to improved cardiometabolic health in people with habitual short sleep durations. Early progress demonstrates proof-of-principle that omics-based technologies are a viable approach to create biochemical signatures (biomarkers) of short sleep duration, primarily derived from acute studies of experimental sleep restriction. Yet, much work remains. Notably, studies that translate early findings from experimental sleep restriction to free-living adults with habitual short sleep duration have high potential to advance the field. Such studies also create an exciting opportunity for larger randomized controlled trials that simultaneously identify biomarkers of habitual short sleep duration and evaluate the efficacy of sleep-based interventions. Ultimately, early progress in developing molecular biomarkers of short sleep duration combined with the prior decades of progress in the sleep and metabolism fields provide the foundation for exciting progress in the biomarker development space.