Background <p>Neuromodulator treatments are widely accepted, highly popular and represent a&#xa0;hallmark of every aesthetic-oriented minimally invasive practice. Despite its limited adverse events profile, some unexpected negative clinical outcomes have been reported.</p> Objective <p>The goal of this work is to better understand the relationship between underlying anatomy and the occurrence of adverse events.</p> Methods <p>This article is designed as a&#xa0;narrative anatomic review summarizing the current anatomic literature and comparing it to the most frequently observed adverse events following treatment with neuromodulators.</p> Results <p>Eyebrow ptosis occurs most frequently when the injections are performed too far caudal, whereas eyelid ptosis can occur when the product is injected too deep. Asymmetric lip position can occur when the risorius or the depressor labii inferioris muscle are inadvertently targeted. Difficulties during swallowing or head anteflexion is most likely related to the administration of product into the deep layers of the neck (instead of the subdermal layer), thereby affecting the muscles deep to the platysma.</p> Conclusion <p>Knowledge of the three-dimensional facial anatomy is crucial when it comes to treatment with neuromodulators and should replace the previous concepts of two dimensions. Knowing that facial muscles are three- and not two-dimensional will guide practitioners toward safer procedures with less collateral damage and an increased safety profile when reducing facial rhytids with neuromodulators.</p>