Since the first mass vaccination against smallpox and its eventual eradication, many more vaccines have been developed based on advances in bacteriology and virology and the use of attenuated live or killed whole pathogens. Immunological discoveries have allowed the development of more refined anti-toxin and conjugate vaccines, while biotechnology provided the tools for rationally designed, genetically engineered vaccines. Many challenges remain in developing safer and more effective vaccines against the more complex diseases such as tuberculosis and HIV-AIDS, and for the rapid protection against newly emerging pathogens or pathogen strains. These vaccines are likely to require the isolation of the "protective" antigenic molecules from the whole pathogen, as well as ways to deliver these to induce effective immune responses with minimal side effects. It has long been recognized that most antigens require the addition of an "adjuvant," an ill-defined substance that non-specifically triggers the innate immune system and boosts an immune response, with aluminum-based adjuvants the most commonly used in most present vaccines. Recent immunological breakthroughs have uncovered that the innate immune system has a much higher degree of complexity than previously thought and can be activated along a wide range of different pathways, depending on the engagement of different innate immune receptors. This in turn determines the type of immune response that will be generated against the vaccine antigens or pathogens. Harvesting the complexity and exquisite specificity of this innate immune system has inspired a new direction in vaccine research, towards the generation of novel adjuvant formulations, tailored to induce defined immune responses effective against specific pathogens. This review gives a brief overview of vaccine development and summarizes different aspects of adjuvant formulation that may influence their activity and specificity.