Phage therapy is an exciting strategy against antimicrobial-resistant bacterial infections, but critical knowledge gaps regarding its clinical application persist. Here, we present our Victorian Bacteriophage Therapy Program and unlike most presentations and publications of success stories, we will deep dive into a clinical case of phage therapeutic failure. Through the study of a patient with a life-threatening, chronic bacterial infection who failed phage therapy, we have been able to uncover several important and fascinating biological concepts that have direct translational impact. Using longitudinal clinical samples, we studied the evolution of the infecting bacteria and phage at multiple sites during infection and were able to identify several reasons why phage therapy was not successful in curing this patients infection. The findings of this work highlight the intricate interplay between host immunology, bacterial genetic diversity and phage biology, bearing broad significance for clinical phage therapy in the future.