Investigators who conduct clinical trials of treatments for uncommon conditions face special challenges regarding trial design and execution in addition to the challenges faced by all clinical trial investigators. The Collaborative Ocular Melanoma Study (COMS) currently consists of two multicenter, randomized controlled clinical trials designed to investigate the efficacy of radiotherapy compared to surgery in prolonging the survival of patients with choroidal melanoma, a rare intraocular cancer. Patients with unilateral choroidal melanoma classified as "medium" in size are randomized with equal probability to either enucleation (removal of the eye) or radiation delivered to the tumor by means of a radioactive "plaque" attached by sutures to the scleral surface of the eye over the base of the tumor. Patients with large tumors are randomized with equal probability to either enucleation or a 5 day course of external beam radiation therapy followed by enucleation. Time to death is the primary outcome; patients will be followed for at least 10 years or until death. Quality assurance mechanisms for evaluation, treatment, and follow-up have been implemented. This paper describes the design and methods of the trials, highlights the challenges associated with implementing and conducting the study, and summarizes the current status of the study.