This commentary critically evaluates the limitations of genetic risk predictions in multifactorial disease, with specific reference to age-related macular degeneration (AMD). AMD is a common blinding disease with 33 million people worldwide experiencing vision impairment. Although gene polymorphism combinations infer an up to 50-fold increased risk of developing the disease, we are far from predicting AMD based on genetics. In the case of complex multifactorial disease such as AMD, to have the same predictive certainty that exists for monogenic disorders, we must account for all gene-environment interactions. We discuss sensitive vision tests that reflect causal gene-environment mechanisms and their potential in AMD risk prediction.