Glaucoma is the second leading cause of blindness worldwide. The primary glaucoma risk factor is elevated intraocular pressure. Topical beta-blockers are affordable and widely used to lower intraocular pressure. Genetic variability has been postulated to contribute to interpersonal differences in efficacy and safety of topical beta-blockers. This review summarizes clinically significant polymorphisms that have been identified in the beta-adrenergic receptors (ADRB1, ADRB2 and ADRB3). The implications of polymorphisms in CYP2D6 are also discussed. Although the candidate-gene approach has facilitated significant progress in our understanding of the genetic basis of glaucoma treatment response, most drug responses involve a large number of genes, each containing multiple polymorphisms. Genome-wide association studies may yield a more comprehensive set of polymorphisms associated with glaucoma outcomes. An understanding of the genetic mechanisms associated with variability in individual responses to topical beta-blockers may advance individualized treatment at a lower cost.