Most visual impairment or degenerative originates in the posterior segment of the eye, however, it remains a major challenge to localize on-demand delivery of drugs due to its unique and complex anatomy, metabolic cycles, and limited options of administration route. In this regard, nanomedicine with innate bio-barrier permeability offers a promising approach of improving delivery performance and releasing drugs under the physiological environment of the eye. Based on these advantages, nanomedicine receives tremendous attention in the field of posterior ocular disease treatment via a non-invasive approach, which is expected to significantly improve medical efficiency and experience in the near future. Here, we discuss recent research advances in ocular posterior segment delivery systems based on nanomedicine, including preclinical formulations and indications, along with opportunities and challenges faced in their clinical translation. We also conclude with a perspective on how we envisage the importance of understanding complex barrier functions so as to continue to develop innovative ocular drug delivery systems.