Small viral proteins with cationic domains can be involved in multiple biological processes including cell penetration or interaction with intracellular targets. Within the last two decades several reports indicated that the C-terminus of HIV-1 Vpr is a cell penetrating sequence, a PP2A-dependent death domain and also displays toxicity against Gram-negative E. coli. Interestingly, HIV-1 Vpr, as well as some cationic proteins encoded by different viruses, share similar physical properties with the unique anti-microbial human cathelicidin LL37 peptide. Consistent with these observations, the Viral Quinta Columna Hypothesis predicts that virally-encoded cationic peptides encoded by multiple viruses may at the same time i) behave as new cathelicidin-like viral positive effectors of innate immunity, mainly through electrostatic interactions with microbial walls, and also display specific toxic cellular effects through interactions with specific intracellular targets such as PP2A proteins. In this context, virally-encoded cationic peptides, potentially detectable in biological fluids, may define a new paradigm for a viral control of homeostasis. Finally, we can also predict that characterization of virally encoded sequences with anti-infective effects may serve as template for the design of new efficient therapeutics polypeptides.