ABSTRACT Piscirickettsiosis, caused by the facultative intracellular bacterium Piscirickettsia salmonis , remains the primary infectious disease economically limiting salmonid aquaculture in Chile, while its incidence has also increased in farmed salmonids in Ireland, Scotland, Australia, and Canada in recent years. This comprehensive review synthesizes 181 peer‐reviewed publications (2014–2026) to integrate transformative advances in P. salmonis genomics, pathogenesis, epidemiology, host immunity, and control strategies, updating the foundational 2014 review by Rozas and Enríquez. Comparative genomic studies have consistently resolved LF‐89‐like and EM‐90‐like isolates as two distinct phylogenomic clusters, with marked differences in pan‐genome composition, lineage‐specific proteins, ribosomal operon organization, and Dot/Icm‐associated genomic architecture, supporting genogroup‐level divergence that should not be inferred from any single threshold‐based metric such as Average Nucleotide Identity (ANI) alone. Genogroup‐specific disease phenotypes are also well established. LF‐89 produces chronic granulomatous infections, whereas EM‐90 causes acute hemorrhagic septicemia. Mechanistically, P. salmonis evades cell‐mediated immunity by inhibiting phagosome–lysosome fusion and suppressing MHC‐I–mediated antigen presentation, impairing CD8 + cytotoxic T‐lymphocyte priming and likely explaining the consistently low vaccine efficacy and genogroup‐restricted cross‐protection observed under field conditions. Treatment failures persist despite absent widespread acquired resistance, attributable to intracellular persistence, biofilm formation, and pharmacokinetic–pharmacodynamic mismatches. Despite exponential growth in mechanistic knowledge, a substantial translational gap persists between research findings and operational implementation. This review identifies critical priorities requiring urgent investment: genogroup‐specific bivalent vaccine development, climate‐adaptive biosecurity frameworks, molecular diagnostic standardization for real‐time genogroup surveillance, and integrated control strategies tailored to P. salmonis genomic heterogeneity.