Traversal of pathogen across the blood–brain barrier (BBB) is an essential step for central nervous system (CNS) invasion. Pathogen traversal can occur paracellularly, transcellularly, and/or in infected phagocytes (Trojan horse mechanism). To trigger the translocation processes, mainly through paracellular and transcellular ways, interactions between protein molecules of pathogen and BBB are inevitable. Simply, it takes two to tango: both host receptors and pathogen ligands. Underlying molecular basis of BBB translocation of various pathogens has been revealed in the last decade, and a plethora of experimental data on protein–protein interactions has been created. This review compiles these data and should give insights into the ligand–receptor interactions that occur during BBB translocation. Further, it sheds light on cell signaling events triggered in response to ligand–receptor interaction. Understanding of the molecular principles of pathogen–host interactions that are involved in traversal of the BBB should contribute to develop new vaccine and drug strategies to prevent CNS infections.