Viruses evolve to evade prior immunity, causing significant disease burden. Vaccine effectiveness deteriorates as pathogens mutate, requiring redesign. This is a problem that has grown worse due to population increase, global travel, and farming practices. Thus, there is significant interest in developing broad-spectrum vaccines that mitigate disease severity and ideally inhibit disease transmission without requiring frequent updates. Even in cases where vaccines against rapidly mutating pathogens have been somewhat effective, such as seasonal influenza and SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2), designing vaccines that provide broad-spectrum immunity against routinely observed viral variation remains a desirable but not yet achieved goal. This review highlights the key theoretical advances in understanding the interplay between polymorphism and vaccine efficacy, challenges in designing broad-spectrum vaccines, and technology advances and possible avenues forward. We also discuss data-driven approaches for monitoring vaccine efficacy and predicting viral escape from vaccine-induced protection. In each case, we consider illustrative examples in vaccine development from influenza, SARS-CoV-2, and HIV (human immunodeficiency virus)—three examples of highly prevalent rapidly mutating viruses with distinct phylogenetics and unique histories of vaccine technology development.