Over the past decade, growth in the number and types of aesthetic procedures performed using botulinum neurotoxin has increased, along with the number of these products. As more options, along with emerging counterfeit agents, become available to clinicians, differences among preparations need to be considered in order to ensure optimal outcomes for patients. Once injected into the muscle, botulinum neurotoxin distributes within that tissue to produce the desired local effects. Diffusion, or the distribution of product beyond the target muscle, can be of concern because of the potential for local and systemic effects that result in muscle weakening away from the desired site. Several factors influence diffusion, including preparation characteristics (e.g. molecular size and structure), dosing and injection technique, and muscles injected. In this article, we discuss the accumulating preclinical and clinical data that differentiate botulinum neurotoxin agents with respect to their diffusion characteristics.