The treatment and prevention of atrial fibrillation (AF) remains a significant unmet medical need. Existing therapies that maintain or restore sinus rhythm (rhythm control) have deleterious effects on the ventricle. A major goal for finding new AF therapies is the identification of repolarization mechanisms that are present in the atrium and not in the ventricle. The potassium current I(Kur) has been shown to be selectively involved in atrial repolarization in human tissue. Hence this current and specifically Kv1.5, the protein that underlies it, have become prime targets for the invention of new AF agents. This article reviews the development of Kv1.5 blockers. The discovery and clinical progress of the non-selective Kv1.5 blockers vernakalant and AVE-0118 are highlighted. More selective Kv1.5 blockers in pre-clinical stages of discovery are then reviewed, with a focus on compounds that have been investigated for their in vivo effects on atrial repolarization or on efficacy in pre-clinical models of atrial fibrillation.