There were four human coronaviruses, HKU1, 229E, NL63, and OC43, that circulate endemically causing relatively mild respiratory disease. During any given “flu season”, endemic human coronaviruses are responsible for up to 30% of common colds. The juxtaposition with SARS-CoV-2 as the fifth endemic coronavirus raises questions about endemic coronaviruses that were previously understudied. Pandemic preparedness led to the rapid development of highly effective COVID vaccines, and while we continue our pandemic preparedness work, we also explore the antigenic landscape of endemic coronaviruses towards “endemic preparedness”. We are dissecting the antigenic landscape of endemic coronaviruses by identifying and characterizing functional receptors, co-receptors, and attachment factors, deciphering the influence of immune responses on the clinical outcome following natural viral infection, isolating and characterizing monoclonal antibodies against endemic coronaviruses, and designing and evaluating vaccines that encompass endemic coronavirus antigens.