Many viruses utilize the lymphohematogenous route for dissemination; however, they may not freely use this highway unchecked. The reticuloendothelial system (RES) is an innate defense system that surveys circulating blood, recognizing and capturing viral particles. Examination of the literature shows that the bulk of viral clearance is mediated by the liver; however, the precise mechanism(s) mediating viral vascular clearance vary between viruses and, in many cases, remains poorly defined. Herein, we summarize what is known regarding the recognition and capture of virions from the circulation prior to the generation of a specific antibody response. We also discuss the consequences of viral capture on viral pathogenesis and the fate of the captor cell. Finally, this understudied topic has implications beyond viral pathogenesis, including effects on arbovirus ecology and the application of virus-vectored gene therapies.