With advances in imaging technology, there has been a significant increase in the number and range of interventional musculoskeletal image-guided procedures. One of the most commonly performed image-guided musculoskeletal interventions is the diagnostic and therapeutic percutaneous aspiration and drainage of multiple types of intra-articular, juxta-articular, and intramuscular pathologic fluid collections. These procedures may be performed under fluoroscopic, ultrasound, computed tomography, or even magnetic resonance guidance depending on the location to be accessed, type of pathology, patient characteristics, and operator preference. Musculoskeletal image-guided aspiration and drainage procedures are minimally invasive and generally very safe while offering valuable diagnostic information as well as therapeutic benefit. This article focuses on the appropriate indications, contraindications, and general technique for accessing the major joints via imaging guidance. For each joint, we discuss pertinent anatomy, appropriate imaging modalities, and preferred approaches to gaining intra-articular access. Additionally, the article discusses some of the more frequently encountered juxta-articular and intramuscular fluid collections that can be accessed and aspirated via percutaneous intervention, with mention of the importance of recognizing extremity sarcomas that can mimic these benign collections.