With 12 available US Food and Drug Administration approved medications for the treatment of relapsing multiple sclerosis (MS), choosing an initial therapy is no longer a straightforward task. Each disease-modifying therapy (DMT) has a distinct risk-benefit profile and each patient is an individual. Therefore, the development of a simple algorithm to apply in selecting initial therapy is not feasible. Instead, the prescribing physician must consider many factors related to the treatments themselves, such as efficacy, safety, and tolerability, while also taking into account a particular patient's disease characteristics, personal preferences, comorbid illnesses and reproductive plans. The efficacy of each drug may be assessed through clinical trial data, although these data are limited by scarcity of direct comparisons among the different agents and lack of availability of biomarkers to predict an individual patient's response. Differences in safety profiles help to distinguish the various DMTs and influence selection of agent; both the known safety concerns, which can be addressed with risk mitigation and monitoring strategies, and the potential for yet undiscovered safety issues must be assessed, and an individual patient's comfort level with the risks and ability to comply with monitoring must be determined. Potential issues related to tolerability, which largely relate to matters of patient personal preference and lifestyle, should also be factored into the decision-making process. With regard to the timing of therapy initiation, it must be acknowledged that long-term benefits of early DMT have not yet been definitively demonstrated. Nonetheless, starting DMT early in the MS disease course has been shown to have a beneficial effect on relapse prevention, and appears to curtail the atrophy and neurodegenerative changes that are now known to begin at disease onset. Although under certain circumstances there are acceptable reasons for deferring treatment, it is generally recommended that DMT is initiated early in the disease course.