Adjuvants are vaccine components that enhance the magnitude, breadth, and durability of the immune response. Since its introduction in the 1920s, insoluble Alum remained the only adjuvant licensed for human use for the next 70 years. However, since the 1990s, a further five adjuvants have been included in licensed vaccines. Yet, the molecular mechanisms by which adjuvants work remains only partially understood. A revolution in our understanding of the molecular pathways of activation of the innate immune system through pattern recognition receptors (PRRs) has allowed a mechanistic understanding of adjuvants, and resulted in the development of adjuvants containing TLR ligands. I will reviewed progress in adjuvant biology, including the notion that tissue damage, different forms of cell death, and metabolic regulators and nutrient sensors, can all profoundly activate the innate immune system and adaptive immunity. Also, recent advances in the use of systems biology to probe the molecular networks driving immune response to vaccines in humans is revealing new mechanistic insights and providing a new paradigm for the vaccine discovery-development process.