Optimizing erectile dysfunction (ED) remains a clinically significant endeavor as insufficient outcomes from oral, injectable and even surgical approaches to treatment remain less than ideal. In this report, we integrate evolving knowledge and provide an algorithmic approach for the clinician to fine-tune management. We performed a PubMed and Medline search of Erectile Dysfunction treatment optimization, enhanced patient efficacy for ED, and why men fail ED treatment. All relevant papers for the past two decades were reviewed. Establishing the goals and objectives of the patient and partner while providing detailed instructions for treatment can minimize failures and create an environment that allows treatment optimization. A thorough work-up may identify reversible or contributing causes. We identified several areas where treatment of ED could be optimized. These include; management of associated medical conditions, lifestyle improvements, PDE5 inhibitor prescription strategies, management of hypogonadism and the initiation of intracavernosal injection therapy (ICI). In our view, once a man presents for help to the clinician, use of the simple strategies identified in this review to optimize the tolerability, safety and effectiveness of the selected treatment should result in enhanced patient and partner satisfaction, with improved outcomes.