Herpes simplex keratitis (HSK) caused by herpes simplex virus type 1 (HSV-1) is a major cause of infectious corneal blindness in developed countries. The disease reflects a variable combination of viral replication, immune-mediated inflammation and neurotrophic dysfunction, whose respective contributions determine both the clinical presentation and therapeutic strategy. Standard management relies on antiviral agents to suppress viral replication, corticosteroids to control immune stromal involvement and ocular surface optimisation to address chronic inflammation and neurotrophic impairment. Refractory forms, defined by a lack of clinical improvement despite appropriate treatment, require reassessment of adherence, pharmacokinetic exposureand underlying pathophysiology. In such cases, antiviral dose adjustment, the use of steroid-sparing immunomodulators and rigorous control of ocular surface inflammation are essential. Neurotrophic keratopathy may benefit from growth factor-based therapies, autologous serum, recombinant nerve growth factor or scleral lenses. The emergence of acyclovir-resistant HSV-1 strains, particularly in immunocompromised or long-term treated patients, represents an increasing concern. In these situations, alternative agents such as trifluridine, foscarnet or more recently, helicase-primase inhibitors, including amenamevir, have demonstrated clinical efficacy. The new strategies outlined here will all provide benefit in treating the drivers of refractory HSK, to quickly resolve and reduce risk of recurrence, providing new opportunities to prevent vision loss in refractory and antiviral-resistant cases.