The plasticity and dynamism in the immune responses to both self and environmental stimulation promote the maintenance and adaptation of a system that tends to harmoniously survive and evolve. Fluctuating antigenic forces coexist within the immune system and oscillate between order and chaos to the equilibrium. Thus, when mounting a response to internal or environmental antigens, the main host responses can be divided into two immunological categories. The first, a well-adapted mechanism of complex multi-cellular organisms classically known as tolerance, promotes persistent immunological responses. In the second, opposite way, the modulation of inflammatory immune responses occurs, which we call “intolerance”. Tolerance and intolerance can be mediated by humoral molecules, such as inflammatory compounds, complement, and antibodies, and by different cell types, such as sentinel cells, antigen-presenting cells, and cells that orchestrate the immune response. Tolerogenesis is important in vertebrates because it predisposes species to adapt to self and environmental negative-selective forces. This process depends, in large part, on antigenic co-stimulation (AgCS), which operates as a multi-integrated network formed by all immune and non-immune cells of the body that establishes tolerant immunoregulatory interactions from cells to cells and from cells to the environment. Antigenic distribution, quantity, nature, route of administration, and antigenic convergence on co-stimulatory pathways, and concurrent infections, and the presence of microorganisms (commensals and pathogens) in more than one site are important factors for activating AgCS. To conclude, the AgCS route is a natural immune response generated by heterogeneous APC profile with centralized regulation that promote the counterbalance between intolerant e tolerant status, which can have several applications in the medical and biological fields.