The eye is one a unique sophisticated human sense organ with a complex anatomical structure. It is encased by variety of protective barriers as responsible for vision. There has been a paradigm shift in the prevalence of several major vision threatening ocular conditions with enhanced reliance on computer-based technologies in our workaday life and work-from-home modalities although aging, pollution, injury, harmful chemicals, lifestyle changes will always remain the root cause. Treating posterior eye diseases is a challenge faced by clinicians worldwide. The clinical use of conventional drug delivery systems for posterior eye targeting is restricted by the ocular barriers. Indeed, for overcoming various ocular barriers for efficient delivery of the therapeutic moiety and prolonged therapeutic effect requires prudent and target-specific approaches. Therefore, for efficient drug delivery to the posterior ocular segment, advancements in the development of sustained release and nanotechnology-based ocular drug delivery systems have gained immense importance. Therapeutic efficacy and patient compliance are of paramount importance in clinical translation of these investigative drug delivery systems. This review provides an insight into the various strategies employed for improving the treatment efficacies of the posterior eye diseases. Various drug delivery systems such as systemic and intraocular injections, implants have demonstrated promising outcomes, along with that they have also exhibited side-effects, limitations and strategies employed to overcome them are discussed in this review. The application of artificial intelligence-based technologies along with an appreciation of disease, delivery systems, and patient-specific outcomes will likely enable more effective therapy for targeting the posterior eye segment.