In conjugate, inactivated, recombinant, and toxoid vaccines, adjuvants are extensively and essentially used for enhanced and long-lasting protective immune responses. Depending on the type of diseases and immune responses required, adjuvants with different design strategies are developed. With aluminum salt-based adjuvants as the most used ones in commercial vaccines, other limited adjuvants, e.g., AS01, AS03, AS04, CpG ODN, and MF59, are used in FDA-approved vaccines for human use. In this paper, we review the uses of different adjuvants in vaccines including the ones used in FDA-approved vaccines and vaccines under clinical investigations. We discuss how adjuvants with different formulations could affect the magnitude and quality of adaptive immune response for optimized protection against specific pathogens. We emphasize the molecular mechanisms of various adjuvants, with the aim to establish structure-activity relationships (SARs) for designing more effective and safer adjuvants for both preventative and therapeutic vaccines.