Viral quantification or viral load testing has become part of the routine management of patients infected with HIV-1 or hepatitis C virus (HCV). There are currently several molecular technologies that are available for use in the clinical laboratory setting. Of these, only the branched DNA (bDNA) assays are FDA-approved for HIV-1 and HCV viral load testing. This signal amplification technology is built on a series of hybridization reactions that are highly amenable to full automation and thus lessen the amount of labor required to perform this type of analysis. This article provides a historical perspective of bDNA and its clinical applications.