Most vaccines require multiple doses to induce long-lasting protective immunity in a high frequency of vaccines, and to ensure strong both individual and herd immunity. Repetitive immunogenic stimulations not only increase the intensity and durability of adaptive immunity, but also influence its quality. Several vaccine parameters are known to influence adaptive immune responses, including notably the number of immunizations, the delay between them, and the delivery sequence of different recombinant vaccine vectors. Furthermore, the initial effector innate immune response is key to activate and modulate B and T cell responses. Optimization of homologous and heterologous prime/boost vaccination strategies requires a thorough understanding of how vaccination history affects memory B and T cell characteristics. This requires deeper knowledge of how innate cells respond to multiple vaccine encounters. Here, we review how innate cells, more particularly those of the myeloid lineage, sense and respond differently to a 1st and a 2nd vaccine dose, both in an extrinsic and intrinsic manner. On one hand, the presence of primary specific antibodies and memory T cells, whose critical properties change with time after priming, provides a distinct environment for innate cells at the time of re-vaccination. On the other hand, innate cells themselves can exert enhanced intrinsic antimicrobial functions, long after initial stimulation, which is referred to as trained immunity. We discuss the potential of trained innate cells to be game-changers in prime/boost vaccine strategies. Their increased functionality in antigen uptake, antigen presentation, migration, and as cytokine producers, could indeed improve the restimulation of primary memory B and T cells and their differentiation into potent secondary memory cells in response to the boost. A better understanding of trained immunity mechanisms will be highly valuable for harnessing the full potential of trained innate cells, to optimize immunization strategies.