Viral receptor blockage by monoclonal antibodies (mAbs) is a common strategy to inhibit viral infection; however, no drug candidate acting by this mechanism has reached the market so far. Analysis of the experimental and clinical data on a receptor-blocking mAb, mAb 1A6, against human rhinovirus (HRV) major receptor intercellular adhesion molecule 1 (ICAM-1) reveals that insufficient avidity of the mAb is probably the key factor to blame for its unsatisfactory clinical efficacy. In this article, we have summarized the recently published work from Perlan Therapeutics, Inc. and others that involves creation of multivalent Fab fusion proteins against the HRV major receptor ICAM-1. The multivalent Fab fusion proteins have exhibited much improved avidities over conventional mAbs, as well as superior HRV inhibition in vitro. This work has led to a promising drug candidate, CFY196, for prevention and treatment of HRV infections. Multivalent recombinant Fab fusion proteins may herald a new generation of potent antiviral receptor blockers and other therapeutic molecules.