The article discusses the critical role of adjuvants in modern vaccines, highlighting their importance in enhancing immune responses and addressing unmet clinical needs. Adjuvants, which can be defined as components that enhance or shape antigen-specific immune responses, have evolved from natural to defined formulations. The review outlines the benefits of adjuvants, including dose sparing, enabling rapid immune responses, broadening antibody responses, and improving the magnitude and functionality of antibody responses. It also emphasizes the need for comprehensive data on safety, tolerability, and efficacy in clinical development. The article details the different classes of adjuvants, such as immunomodulatory molecules, delivery systems, and combinations of these, and their mechanisms of action. Key mechanisms include activation of innate immune receptors, modulation of antigen presentation, and recruitment of immune cells. The selection of adjuvants is influenced by factors such as vaccine antigen properties, desired immune responses, target population, and administration route. Recent advancements in understanding the mechanisms of action of adjuvants, such as aluminum salts and oil-in-water emulsions, are discussed, along with the challenges in translating preclinical data to clinical use. The article also highlights the importance of systems vaccinology in predicting immune responses and adverse events, and the need for further research to optimize adjuvant formulations. Finally, the article explores future directions in adjuvant development, including the targeting of dendritic cells and the induction of mucosal immunity, and emphasizes the potential of defined adjuvants with better-understood mechanisms to enhance vaccine efficacy and reduce side effects.The article discusses the critical role of adjuvants in modern vaccines, highlighting their importance in enhancing immune responses and addressing unmet clinical needs. Adjuvants, which can be defined as components that enhance or shape antigen-specific immune responses, have evolved from natural to defined formulations. The review outlines the benefits of adjuvants, including dose sparing, enabling rapid immune responses, broadening antibody responses, and improving the magnitude and functionality of antibody responses. It also emphasizes the need for comprehensive data on safety, tolerability, and efficacy in clinical development. The article details the different classes of adjuvants, such as immunomodulatory molecules, delivery systems, and combinations of these, and their mechanisms of action. Key mechanisms include activation of innate immune receptors, modulation of antigen presentation, and recruitment of immune cells. The selection of adjuvants is influenced by factors such as vaccine antigen properties, desired immune responses, target population, and administration route. Recent advancements in understanding the mechanisms of action of adjuvants, such as aluminum salts and oil-in-water emulsions, are discussed, along with the challenges in translating preclinical data to clinical use. The article also highlights the importance of systems vaccinology in predicting immune responses and adverse events, and the need for further research to optimize adjuvant formulations. Finally, the article explores future directions in adjuvant development, including the targeting of dendritic cells and the induction of mucosal immunity, and emphasizes the potential of defined adjuvants with better-understood mechanisms to enhance vaccine efficacy and reduce side effects.