Plasmin is the final product of the fibrinolytic system, the physiological mechanism responsible for dissolving fibrin clots. Its broad-range proteolytic activity implies that interaction with fibrinolysis and recruitment of plasmin by blood and tissue parasites is an important mechanism that mediates the invasion and establishment of this kind of pathogen in the hosts. However, recent studies have linked an excess of plasmin generated by this interaction with serious pathological events at the vascular level, including the proliferation and migration of arterial wall cells, inflammation, and degradation of the extracellular matrix. Therefore, we present data that support the need to reconsider the role of plasmin, as well as its benefits or drawbacks, in the context of host-parasite relations.