The standard therapeutic approach for advanced ovarian cancer is upfront cytoreductive surgery followed by a combination of platinum and taxane-based chemotherapy. Since patients with complete tumor resection (R0) appear to have the best overall outcomes, efforts to spare unnecessary primary debulking surgery by pre- or intra-operative assessment have abounded without external validity to incorporate into general practice. Serum CA125, physical examination and CT imaging have lacked accuracy in determining if disease can be optimally debulked. Therefore, an algorithm that identifies patients likely to achieve complete gross resection at primary surgery would be expected to improve patient survival. Herein, we will present contemporary definitions of “optimal” residual disease, and discuss opportunities to personalize surgical therapy and improve the quality of surgical care delivered to patients with advanced ovarian cancer. Such a standardized approach also offers unique opportunities for novel clinical trial designs that allow for rigorous testing of relevant biomarkers. Moreover, with the massive expansion of the knowledge related to ovarian cancer biology, new therapies aimed at angiogenesis, DNA damage repair and other pathways hold tremendous potential for improving therapeutic outcomes. Unique opportunities for targeting traditionally undruggable targets using RNA interference and biocompatible nanoparticle strategies have been introduced into clinical testing. Collectively, these approaches offer many opportunities for personalized medicine and improving patient survival while reducing toxicities