No medical procedure has saved more lives than vaccination. But, today, some pathogens have evolved which have defied successful vaccination using the empirical paradigms pioneered by Pasteur and Jenner. I will describe how bringing together theoretical/computational approaches from statistical physics and engineering with basic/clinical immunology is beginning to confront this challenge by developing some of the ingredients necessary for rational design of vaccines that can confront these scourges. One characteristic of many pathogens for which successful vaccines do not exist is that they present themselves in various guises. HIV is an extreme example because of its high mutability, and it continues to wreak havoc around the world, especially in developing countries. I will describe how we developed models to translate data on HIV protein sequences to knowledge of the HIV fitness landscape, and tested the results against in vitro and clinical data. Based on these results, a therapeutic T cell-based vaccine was designed, which is now being advanced to pre-clinical studies in monkeys. I will also describe work pertinent to how broadly neutralizing antibodies, which can neutralize diverse HIV strains, might be induced by vaccination.