Preventative medicine in the form of vaccination had a huge impact on human health in the 20th Century. Vaccines are now recognized as the most effective line of defence against infectious agents that cause disease and death, and in some cases vaccines have enabled complete eradication of disease from the globe (e.g. smallpox). Nevertheless there are still many human diseases (e.g. viral and parasitic infections, cancers) for which there are no effective vaccines. Current vaccines are mainly live and attenuated viruses or viral, bacterial or recombinant proteins and polypeptides. By virtue of their natural aminoacid composition, polypeptides and proteins are relatively safe materials for vaccination, but they are expensive to manufacture making them inaccessible to the most vulnerable and needy human populations that cannot afford such medicines. This review will focus on shorter synthetic peptides that are cheaper to manufacture, conceivably even safer for human use because of increased specificity, but they also suffer from problems that have presumably resulted in their lack of progress in clinical trials. Since 1990, over 100 chemically synthesized short peptide vaccines have entered Phase I clinical trials, less than 20 have progressed into Phase II, but none have entered Phase III clinical trials. In this review we discuss reasons why vaccines based on short peptides may not have succeeded in the clinic, identify problems such as insufficient immunogenicity, structural/conformational instability, chemical instability due to degradation, and describe possible solutions to some of these problems that have been investigated in recent years.