The interaction between a viral ligand and its cellular receptor is highly specific and limits host range. A recent paper describes a mutant form of bacteriophage λ that targets an alternative receptor after co-evolution with Escherichia coli. When phage cI26 was cultured with E. coli in conditions that sustained the phage but suppressed expression of the canonical host receptor, LamB (also known as maltoporin), mutant phage particles shifted their specificity from LamB to a new receptor, OmpF. A combination of four mutations in the phage tail protein J were essential for exclusive targeting of OmpF and were present in multiple lineages, an indicator of strong positive selection. Interestingly, not all lineages evolved the capacity to use OmpF, and the authors found that the evolutionary trajectory demanded a fortuitous sequence of mutational events, not only in the phage but also its host, demonstrating the complexity of interactions in a co-evolving population.