Recently, I attended the Modern Vaccines Adjuvants and Delivery Systems conference held in Leiden, The Netherlands (May 18-20, 2015); which highlighted some of the major challenges in the development of efficacious vaccines and their effective delivery for both (re) emerging infectious diseases and endemic Neglected Tropical Diseases (NTDs). These infections include not only the “big three” of Malaria, HIV/AIDS and Tuberculosis, but also Leishmaniasis, Ebola, MERSCOV, helminths and others. Notably, for the “big three” attempts to develop such vaccines have been largely disappointing. Some of the challenges lie with the extreme genetic variability of the pathogens. Most successful vaccines have been against slowly evolving pathogens with a limited number of antigenically different strains that induce immune responses dependent on neutralizing antibodies; a mechanism that is well understood. Also, for most vaccine preventable diseases, natural infections with their pathogens leave the host (temporarily, partially) immune to reinfection or disease with the same (strain of) pathogen. The danger of these pathogens is that they often win the race between their own rapid rate of multiplication and the host response which depends on immune recognition and activation and proliferation of immune cells, specifically-B cells. Once the host mounted an immune response and survived the fight he has won the race. Most of the infections above, however, do not conform to that pattern. In TB, cellular mechanisms are essential for controlling the infection, but do not eliminate it. The pathogens, Mycobacterium tuberculosis (Mtb), reproduce very slowly and disease occurs, if at all (in a minority of infections), months or years after infection. Disease, once cured, does not offer protection against reinfection or disease from reinfection. Speed of immune recognition seems to play no role, as most individuals who develop TB have detectable (by IGRA or TST) immune responses to the pathogens. Rather, it seems, a failure of the cellular effector mechanisms is at fault, and if so the prospects for an effective vaccine that protect against disease are slim. As neutralizing antibodies play no role in protection, also the prospects of conferring protection against (re) infection seem equally poor. Immune mechanisms against malaria and HIV are also complex and poorly understood, and attempts to develop an HIV vaccine have been graphically called “shots in the dark” [1]. The more I learn about vaccines and vaccination, the more I become perplexed, less optimistic, but also fascinated. Despite the stunning recent advances in immunology and medical research why do we still fail, and what are the missing scientific links? Are vaccines for some infections simply impossible, or are we simply not aiming our efforts correctly? Progress seems increasingly difficult, but the rewards of success, therefore so huge. The English physician Edward Jenner developed (or rather discovered) that cowpox offered a relatively safe alternative to the risky practice of variation in 1796 and in 1977 smallpox was eradicated worldwide. On May 8, 1980, the World Health Assembly announced that the world was free of smallpox and recommended that all countries cease vaccination: “The world and all its people have won freedom from smallpox, which was the most devastating disease sweeping in epidemic form through many countries since earliest times, leaving death, blindness and disfigurement in its wake” [2]. Jenner just observed, but knew nothing about viruses, let alone immunology.