The search for a human immunodeficiency virus (HIV) vaccine has spanned nearly four decades without much success. A much needed paradigm shift can be found in the abnormally high levels of intrinsic disorder in the outer shells of HIVs, the hepatitis C virus (HCV), and herpes simplex viruses (HSVs), for which successful vaccines have not been established. On the other hand, this feature (high levels of intrinsic disorder in the outer shells) is completely absent in classic viruses for which effective vaccines are found, such as the rabies virus. The motions arising from the disordered outer shell result in the inability of antibodies to bind tightly to the polysaccharides on the viral surface proteins, and, therefore, induce inadequate immune response. Experiments conducted by the legendary Avery Oswald in the 1920s form the theoretical underpinning of this new model. Failures of the vaccines based on the HIV glycoprotein Gp120 and other vaccines can be traced back to the lack of understanding of the important roles of shell disorder in a “Trojan-horse” immune evasion mechanism utilized by the virus. Communicated by Ramaswamy H. Sarma.