PDZ proteins are highly conserved through evolution; the principal function of this large family of proteins is to assemble protein complexes that are involved in many cellular processes, such as cell‐cell junctions, cell polarity, recycling, or trafficking. Many PDZ proteins that have been identified as targets of viral pathogens by promoting viral replication and spread are also involved in epithelial cell polarity. Here, we briefly review the PDZ polarity proteins in cells of the immune system to subsequently focus on our hypothesis that the viral PDZ‐dependent targeting of PDZ polarity proteins in these cells may alter the cellular fitness of the host to favor that of the virus; we further hypothesize that this modification of the cellular fitness landscape occurs as a common and widespread mechanism for immune evasion by viruses and possibly other pathogens.—Gutiérrez‐González, L. H., Santos‐Mendoza, T. Viral targeting of PDZ polarity proteins in the immune system as a potential evasion mechanism. FASEB J. 33, 10607–10617 (2019). www.fasebj.org