This review article provides an overview of the evolution of diphtheria vaccine, its value and its future. Diphtheria is an infectious illness caused by diphtheria toxin produced by pathogenic strains of Corynebacterium diphtheriae. It is characterized by a sore throat with membrane formation due to local tissue necrosis, which can lead to fatal airway obstruction; neural and cardiac damage are other common complications. Diphtheria vaccine was first brought to market in the 1920s, following the discovery that diphtheria toxin can be detoxified using formalin. However, conventional formalin-inactivated toxoid vaccines have some fundamental limitations. Innovative technologies and approaches with the potential to overcome these limitations are discussed in this paper. These include genetic inactivation of diphtheria toxoid, innovative vaccine delivery systems, new adjuvants (both TLR-independent and TLR-dependent adjuvants), and heat- and freeze-stable agents, as well as novel platforms for producing improved conventional vaccine, DNA vaccine, transcutaneous (microneedle-mediated) vaccine, oral vaccine and edible vaccine expressed in transgenic plants. These innovations target improvements in vaccine quality (efficacy, safety, stability and consistency), ease of use and/or thermal stability. Their successful development and use should help to increase global diphtheria vaccine coverage.