Only a few techniques are currently available for quantifying systemic metastases in preclinical models. Cancer cell expression of naturally secreted Gaussia luciferase (Gluc) provides a useful circulating biomarker that enables the monitoring of metastatic tumor burden and of treatment response from minimal drops of blood. This blood-based Gluc assay exhibits several distinct advantages: (1) It is highly sensitive in quantifying metastatic tumor growth, particularly when compared to whole-body bioluminescence imaging (BLI) alone; (2) It is quantitative by nature and reflects viable tumor burden in a minimally invasive manner; (3) Through longitudinal collection of blood samples, treatment response can be monitored in real-time; and (4) Gluc bioluminescence provides a means to localize and assess metastatic colonization using BLI. By elucidating the progression of systemic metastases and therapeutic response in animal models, the blood-based Gluc assay is emerging as a valuable quantitative tool for novel drug development.