Adjuvants, substances included in many vaccines in order to improve immune responses, are challenging to develop and license because adjuvant compounds that stimulate strong protective immunity also frequently induce significant toxicity. Adjuvant design and development has until recently been largely empirical; but with the current knowledge that most adjuvants act via receptors of the innate immune system, molecular-based approaches are rapidly advancing the field. Data support the concept that proinflammatory pathways induced by innate immune receptor triggering underlie many of the observed toxic effects. Importantly, the cellular signaling pathways that lead to inflammation are known, for a number of innate immune receptors, to be distinct from those that are involved in the costimulation of protective adaptive immune responses, leading to approaches for attenuating inflammatory signaling that should lead to safer and more effective vaccine adjuvants. This article addresses whether there is a clear rationale for the separation of toxicity from efficacy in the function of adjuvants based upon innate immune receptor ligands.