The production of tilapia Oreochromis spp. is rapidly growing throughout the world, but atypical motile aeromonad septicemia (MAS) is a current threat to the tilapia farming industry. The etiological agent of this disease is usually Aeromonas hydrophila. Mortality rates due to MAS are frequently high, resulting in a devastating negative impact on this industry worldwide; therefore, proper control measures regarding both prevention and treatment are necessary. Although vaccines against MAS for tilapia are available, their effectiveness is entirely dependent on the specific strain of problematic bacteria. Until now, whole-cell inactivated A. hydrophila vaccines for tilapia have exhibited the highest level of protection over live attenuated and recombinant vaccines. Among the various vaccine administration systems, only intraperitoneal (i.p.) injections of the A. hydrophila vaccine into tilapia were found to provide prominent immune protection. Vaccine efficacy was primarily measured by using the i.p. injection challenge model and estimating the relative percent survival of the immunized tilapia. Freund's incomplete adjuvant showed to be the most effective for tilapia MAS vaccines. In this review, multiple factors that directly or indirectly influence the efficacy of MAS vaccines for tilapia (adjuvants, challenge models, immunization doses and duration, and size of vaccinated fish) are discussed.