Elevated levels of sperm deoxyribonucleic acid (DNA) fragmentation (SDF) have been associated with several adverse reproductive outcomes, including: lower natural and assisted reproductive technology (ART) pregnancy rates, abnormal embryo development, and recurrent pregnancy loss. However, due to conflicting study results, limited high-level evidence, multiple clinically available assays, and variable standard reference ranges, precisely how SDF testing should be applied to the evaluation and treatment of infertile men remains controversial. To better understand SDF and its role in clinical practice, this chapter aims to: (1) review the literature that has made SDF such a controversial topic, (2) discuss newly published evidence contributing to this complex discussion, and (3) outline the most recent practice guidelines currently available.