Carpal tunnel syndrome is the most frequent compression neuropathy with an incidence of one to three subjects per thousand. As specific anatomical variations might lead to unintended damage during surgical interventions, we present a review to elucidate the anatomical variability of the carpal tunnel region with important considerations for daily clinical practice: several variants of the median nerve branches in and around the transverse carpal ligament are typical and must – similarly to the variant courses of the median artery, which may be found eccentric ulnar to the median nerve – be taken into account in any interventional therapy at the carpal tunnel. Unintended interference in these structures might lead to heavy arterial bleeding and, in consequence, even underperfusion of segments of the median nerve or, if neural structures such as variant nerve branches are impaired or even cut, severe pain-syndromes with a profound impact on the quality of life. This knowledge is thus crucial for outcome- and safety-optimization of different surgical procedures at the volar aspect of the wrist and surgical therapy of the carpal tunnel syndrome e.g., USguided carpal tunnel release, as injury might result in dysfunction and/or pain on wrist motion or direct impact in the region concerned. For most variations, anatomical and surgical descriptions vary, as official classifications are still lacking.