: The oral route of vaccination is pain- and needle-free and can induce systemic and mucosal immunity. However, gastrointestinal barriers and antigen degradation impose significant hurdles in the development of oral vaccines. Live attenuated viruses and bacteria can overcome these barriers but at the risk of introducing safety concerns. As an alternative, particles have been investigated for antigen protection and delivery, yet there are no FDA-approved oral vaccines based on particle-based delivery systems. Our objective was to discover underlying determinants that can explain the current inadequacies and identify paradigms that can be implemented in future for successful development of oral vaccines relying on particle-based delivery systems.: We reviewed literature related to the use of particles for oral vaccination and placed special emphasis on formulation characteristics and administration schedules to gain an insight into how these parameters impact production of antigen-specific antibodies in systemic and mucosal compartments.: Despite the long history of vaccines, particle-based oral vaccination is a relative new field with the first study published in 1989. Substantial variability exists between different studies with respect to dosing schedules, number of doses, and the amount of vaccine per dose. Most studies have not used adjuvants in the formulations. Better standardization in vaccination parameters is required to improve comparison between experiments, and adjuvants should be used to enhance the systemic and mucosal immune responses and to reduce the number of doses, which will make oral vaccines more attractive.