Viruses rapidly evolve to stay a step ahead of their hosts. Several new variants emerged during the course of pandemics, with Omicron sublineages BQ.1.1 and XBB being the most recent. These variants displayed higher fitness taking over a significant part of the virus population. Although each variant revealed mutations across the whole genome, a significant portion of the phenotype can be attributed to mutations in the Spike protein and its mutational hotspot Receptor Binding Domain (RBD). We study the ongoing evolution and adaptation of SARS-CoV-2 to humans, focusing on the interaction that dictates its immunological properties. Apart from the structural similarity, the interface of SARS-CoV-2 – ACE2 is composed of different amino acids from that of the RBD of SARS-CoV. While both RBDs bind the same location, mostly helix one on the ACE2, they differ in 11 interface residues and the new variants are similarly different. Parallel solutions for the same interaction suggest high interface plasticity. In my talk, I will describe how current in vitro evolution techniques can help explain this observed plasticity and what we have learned about protein interface evolution in general.