The cellular and molecular mechanisms underlying the death of photoreceptors and other retinal cells in age-related macular degeneration (AMD) remain poorly understood. Some of the questions for which answers need to be sought, and which are explicitly or implicitly addressed in this article include: (1) how do patterns of cell death in AMD compare, qualitatively and quantitatively, with "normal" cell death in aging retinas, and with cell death in retinitis pigmentosa (RP) and its animal models; (2) is apoptosis involved in AMD; (3) is there any evidence that rods are necessary for cone survival; (4) if the answer is yes, is there evidence that rods produce one or more survival-promoting factor(s) that act directly on cones; (5) are the effects of rods upon cones exclusively mediated by diffusible factors, or do they also involve contact-mediated interactions; (6) is there any evidence that photoreceptors regulate the survival and/or function of RPE and Müller cells, as well as the interactions between these cells and cones; (7) are trophic factors and their receptors in the macula different from those in other parts of the retina; and (8) are toxic mechanisms involved in the onset and progression of cell death in AMD? Clear cut answers to most of these (and related) questions about cell death in AMD are not yet available. The goal of this article is to summarize discussion that should help in the formulation of suitable hypotheses, amenable to experimental analysis. To provide a platform for such discussion, we present an overview of progress made in recent years in the analysis of other retinal degenerations and of neuronal degenerations in other regions of the CNS. We conclude with an overview of concepts and speculation derived from our current research.