In most of the Western world, age-related macular degeneration (AMD) remains the largest single cause of severe visual impairment, and its prevalence continues to increase. It is considered to be a complex disease, in which multiple genes and environment play a role in pathogenesis. Several environmental insults are implicated with smoking, serum cholesterol, hypertension, sunlight exposure, and many other factors being variously associated with disease pathogenesis. Until recently, there have been relatively few breakthroughs to further our understanding of the genetics of AMD, despite remarkable progress in molecular genetic techniques over the last 20 years, and the fact that many rare inherited macular diseases have had their causative genes mapped. Development of new tools such as high-density single-nucleotide polymorphism chips and microarrays have changed the face of genetic research, but have yet to directly translate into improved clinical outcomes in ophthalmology. However with the recent finding of the Tyr402His polymorphism in the complement factor H gene being implicated in AMD, we are about to witness a new wave of research in this disease. Not only does the identification of a biologically plausible gene identify a new pathway, but it also identifies new biological mechanisms for disease, avenues to pursue treatment, and a better understanding of how the environment interacts with the genetic background to create disease. This article aims to review the process of gene discovery in complex disease, why the search for genes remains difficult, how to translate laboratory findings to a clinical setting, and how these findings will impact on disease treatment and public health issues.