During the past few decades, numerous approaches towards therapeutic vaccines have been investigated. In addition to traditional prophylactic vaccines against infectious microorganisms, there have been attempts to develop therapeutic vaccines for indications as complex as autoimmunity and cancer. Driven by an increasing understanding of the underlying mechanisms, researchers have attempted to interfere with complex molecular cascades during disease progression. Monoclonal antibodies have gained more importance, and their specificity has become more predictable. However, in spite of the advances in our knowledge, crucial problems linger unsolved in vaccinology, such as the major histocompatibility complex (MHC) degeneration phenomenon, the escape from immune surveillance of cancer and microbes, and the possibility of adverse events, perhaps linked to peptide cross-reactivity. In essence, it seems that in order to understand immune responses the peptide-peptide interactions have yet to be clearly defined. These issues will be discussed in the frame of current approaches to vaccine development with special focus on cancer vaccines.