Botulinum neurotoxin (BoNT) therapy has expanded from its initial application for ophthalmologic problems (strabismus and blepherospasm) to treating a wide variety of clinical problems including neurological, neurosecretory, gastrointestinal, urologic, musculoskeletal, and pain conditions. This chapter covers examples of specific clinical applications of ultrasound (US) guidance for BoNT therapy including muscle hypertonia, salivary glands, and musculoskeletal conditions. It also discusses US-guided BoNT therapy for other body systems. Real-time US guidance provides the information required to accurately inject these targets including the location and depth of the intended target and structures to be avoided. This precision reduces the inherent risks of these procedures. Additional studies are needed to determine whether the use of US guidance leads to increased efficacy and a reduction of toxin dose. While the use of US guidance for chemodenervation procedures requires learning a new set of skills, these skills enhance patient safety and reduce the risk.