Pathogenic bacteria have evolved multiple mechanisms aimed to evade host defenses. This review summarizes selected examples of how bacteria utilize proteolytic enzymes to efficiently establish and spread infection systemically. First, the role of proteases in intracellular survival and persistence - the primary means used by bacteria to endure phagocytosis and/or avoid the vigilance of the immune system - is discussed. Second, it is demonstrated how some bacteria escape entanglement in fibrin(ogen) meshes, by inducing their proteolytic dissolution while other species modify the proteolytic cascade of mesh formation to divert this important innate immune defense for their own benefit. Third, bacterial proteolytic toxins are introduced, which allow microorganisms to exert and take advantage of systemic effects already during primary, localized infection. Finally, it is discussed how viruses utilize bacterial proteases by taking advantage of concurrent infection, and how pathogens may even mutually benefit from the joint presence of other pathogens. The reviewed adaptations are often essential for pathogen survival in the hostile environment of a host organism. As such, the potential benefits of pharmacological interference in relevant pathways for the struggle against bacterial pathogens are also discussed.