The emergence of wildlife reservoirs of Mycobacterium bovis infection in cattle as well as increased inter-regional trade with associated spread of M. bovis has led to renewed interest in the use of vaccines for the control of bovine tuberculosis (TB). Field efficacy trials performed in the early 20th century demonstrated the partial effectiveness of bacilli Calmette-Guerin (BCG) for the control of bovine TB. Recent experimental trials with cattle have demonstrated that: (1) subunit vaccines may boost immunity elicited by BCG in cattle, (2) T cell central memory immune responses evoked by protective vaccines correlate with protection upon subsequent M. bovis challenge, (3) BCG is particularly protective when administered to neonates, and (4) differentiation of infected from vaccinated animals (DIVA) is feasible in cattle using in vitro or in vivo methods. In regards to wildlife reservoirs, the efficacy of BCG delivered orally has been demonstrated for brushtail possums (in field trials) as well as Eurasian badgers, wild boar, and white-tailed deer (each in experimental challenge studies). Vaccine delivery to wildlife reservoirs will primarily be oral, although a parenteral route is being deployed for badgers in England. Vaccine efficacy trials, both experimental challenge and field studies, with cattle and their wildlife reservoirs represent a primary example of the one health approach, with outcomes relevant for both veterinary and medical applications.