Blood-based biomarkers offer a non-invasive, scalable strategy for HCC screening that can increase sensitivity for early-stage HCC as well as adherence. Tests like GALAD and methylated DNA panels have shown promise in improving sensitivity and specificity compared to ultrasound but require validation prior to routine use. As an NIH-funded as a Clinical Validation Center for Liver Cancer, we are collaborating with academic and industry partners to evaluate several promising blood-based biomarkers in both case-control (phase 2) and cohort (phase 3) studies. We are also leading a randomized clinical trial evaluating biomarker-based screening (with GALAD) compared to ultrasound in >5000 at-risk patients with chronic liver disease.