The COVID-19 pandemic disrupted global health systems but simultaneously offered a rare opportunity to observe the rapid co-evolution of a virus, SARS-CoV-2, with the human immune system in real time. This evolutionary interplay is often thought of as a molecular arms race, in which both pathogen and host must continually adapt to changes in each other’s phenotype. This dynamic is particularly pronounced at the molecular recognition level. Human antibodies evolve (via affinity maturation) to better neutralize the viral antigens (e.g., SARS-CoV-2 spike protein), while the virus, in turn, accumulates mutations that confer immune escape. In this dissertation, I present four projects that explore the co-evolutionary landscape between viral and immune proteins. Chapters 1 and 2 focus on the combinatorial mutagenesis of the SARS-CoV-2 spike receptor-binding domain (RBD) to measure the individual and combined effects of Omicron BA.1 mutations on ACE2 binding affinity (Chapter 1) and antibody evasion (Chapter 2). Chapter 3 extends this approach to later Omicron subvariants, using high-throughput genotype-to-phenotype mapping to investigate how mutational effects depend on genetic background across divergent lineages. Finally, Chapter 4 shifts focus to the host immune response, using deep sequencing of human peripheral blood B cell repertoires and yeast display of candidate antibodies to measure evolving antibody phenotypes. Together, these studies provide an integrated view of viral and immune co-evolution, inferring the molecular principles that govern host-pathogen interactions and the trajectory of viral adaptation.