Infectious diseases represent a major cause of deaths worldwide. No vaccine or effective treatment exists nowadays, especially against intracellular pathogens. The increase in multiple drug and superbug antibiotic resistance strains, excessive medication, or misuse of drugs has prompted the search for other safe and effective alternatives. Consistent with this, adjuvants (Latin word “adjuvare”: “help or aid”) co-administered (Exo) in vaccines have emerged as a promising alternative to initiate and boost an innate, downstream signal that led to adaptative immune response. Nowadays, a promising model of strong immunogens and adjuvants at mucosal sites are the microbial bacterial toxins. Other adjuvants that are also used and might successfully replace aluminum salts in combination with nanotechnology are CpG-ODN, poly IC, type I IFNs, mRNA platforms. Therefore, in the present review, we focused to revisit the old to the new adjuvants compounds, the properties that make them friends in vaccine formulations against infectious diseases.