Annually, carpal tunnel release is one of the most commonly executed orthopaedic procedures. Despite the frequency of the procedure, complications may occur as a result of anatomic variations. Understanding both normal and variant anatomy, including anomalies in neural, vascular, tendinous, and muscular structures about the carpal tunnel, is fundamental to achieving both safe and efficacious surgery. Reviewing and aggregating this information reveals certain principles that may lead to the safest possible surgical approach. Although it is likely that no true internervous plane or so-called safe zone exists during the approach for carpal tunnel release, the long-ring web space axis does appear to pose the lowest risk to important structures.