Viral pathogens, including influenza A virus (IAV) and coronavirus (CoV), have been the source of devastating pandemics and outbreaks, resulting in high morbidity, mortality, and socioeconomic disruptions. Despite advances in new antiviral and therapeutic modalities, the relentless evolution of these viruses necessitates urgent action to devise effective strategies against them. The viral entry process is the initial step in the infection cycle and is a critical determinant of host susceptibility to viral pathogens. By deciphering how viruses breach host defenses to gain entry into cells, potential vulnerabilities can be identified for the development of targeted interventions to prevent or mitigate infection. Viral entry entails two main critical steps: first, the interaction between viral proteins and host receptors, leading to binding of the virion to the plasma membrane of the host. Second, the fusion of the membrane of the virus with that of the host cell to release the viral core into the host cell. These processes are difficult to decouple in live cell studies, so we use a biomimetic platform to specifically focus on the binding and fusion steps. In the first part of this thesis, I set out to understand the impact of a receptor variant common in animal hosts on human IAV entry. Our findings suggest that receptor affinity changes are the major adaptation required, without further adaptation of fusion machinery for the human IAV H3N2 to enter animal hosts, highlighting the low barrier for zoonotic spillover events. In the second part, I investigated how a conserved tyrosine within the fusion peptide (FP) of CoV Spike plays a role in viral entry. Through a blend of biological and biophysical analyses combined with molecular simulations, I was able to unravel the critical role of tyrosine in stabilizing FP conformations for Ca2+ binding, a pivotal step for downstream fusion and infection. These collective findings provide insights into how viral entry and infection are impacted by the changes at the molecular level in the two key components, host receptor and viral protein, suggesting potential targets for developing antiviral measures. Leveraging our fundamental insights for blocking viral entry, we targeted the conserved FP region in the Spike to develop monoclonal antibodies (mAbs) exhibiting anti-fusogenic properties and cross reactivity. Overall, these studies of virus-host interactions provided new insights that were used to guide the development of therapeutics that could ultimately mitigate the impact of viral outbreaks on human health and society.