Transplantation of potentially therapeutic cells into the subretinal space is a promising prospective therapy for the treatment of retinal degenerative diseases including age-related macular degeneration (AMD). In rodent models with photoreceptor degeneration, subretinal transplantation of cell suspensions has repeatedly been demonstrated to rescue behaviorally measured vision, maintain electrophysiological responses from the retina and the brain, and slow the degeneration of rod and cone photoreceptors for extended periods. These studies have led to the initiation of a number of FDA-approved clinical trials for application of cell-based therapy for AMD and other retinal degenerative diseases. However, translation from rodent models directly into human clinical trials skips an important intermediary preclinical step that is needed to address critical issues for intraocular cell transplantation. These include determination of the most appropriate and least problematic surgical approach, the application of treatment in an eye with similar size and structure including the presence of a macula, and a thorough understanding of the immunological considerations regarding graft survival and the consequences of grafted cell rejection. This chapter will review these and related issues and will document current efforts to address these concerns.