The development of methods that enabled genome-wide mapping of DNA G-quadruplex structures in chromatin has played a critical role in providing evidence to support the formation of these structures in living cells. Over the past decade, a variety of methods aimed at mapping G-quadruplexes have been reported in the literature. In this critical review, we have sought to provide a technical overview on the relative strengths and weaknesses of the genomics approaches currently available, offering step-by-step guidance to assessing experimental needs and selecting the most appropriate method to achieve effective genome-wide mapping of DNA G-quadruplexes.