As the number of treatments for relapsing forms of multiple sclerosis (MS) increases, advising newly-diagnosed individuals about how to choose a first therapy is more and more challenging. Each person with MS brings their own unique features to the consideration, including characteristics of their MS, their own opinions and values, and payer factors. Treatments themselves vary in efficacy and effectiveness, and they also have individual side effects and risks that must be considered. In this lecture, we will discuss the concepts of efficacy and effectiveness. We will review the literature addressing the impact of MS therapies on subsequent disability in people with MS. Approaches to choosing a therapy in the modern treatment era will be reviewed, and we will describe ongoing clinical trials, TREAT-MS and DELIVER-MS, that are addressing whether an escalation or early higher-efficacy therapeutic strategy will impact the longer-term prognosis of a person with newly-diagnosed, relapsing MS.