<p>Reverse-phase high-performance liquid chromatography (RP-HPLC) has continued to remain one of the most extensively employed analytical techniques in pharmaceutical analysis, with its high robustness, accuracy, and applicability. However, the traditional RP-HPLC method development process has often been associated with high organic solvent usage, environmental toxicity, and inflexibility in terms of lifecycle approaches. In this context, the relatively new science of Analytical Quality by Design (AQbD), with its potential for the development of robust and flexible analytical procedures, has emerged as an alternative to traditional approaches, with Green Analytical Chemistry (GAC) advocating environmentally friendly analytical approaches. This review article aims to discuss the AQbD-driven RP-HPLC method development process with an increased focus on sustainability and its potential to meet the demands of the regulation.In addition to the conventional sustainability strategies, The review article discusses the subject of White Analytical Chemistry (WAC) in relation to its potential to satisfy regulatory requirements for sustainability using its three-dimensional approach consisting of analytical performance (red), sustainability of the environment (green), and operability (blue). The potential of the WAC approach to satisfy regulatory requirements has been critically discussed in relation to ICH Q14 and Q2(R2). The review article concludes with recommendations and suggestions for future work that may help analysts in the rational and sustainable development of RP-HPLC methods.</p>