This systematic review by Inchingolo et al. explores the intricate relationship between cytokines and orthodontic treatment (OT). Cytokines, low-molecular-weight proteins involved in immune responses, play a crucial role in both innate and acquired immune responses. The review highlights the multifaceted role of cytokines in OT, emphasizing how orthodontic forces induce tension and compression in the periodontal ligament (PDL), leading to the release of cytokines. Proinflammatory cytokines, such as IL-1, IL-6, and TNF, influence bone and soft tissue metabolism, with elevated levels observed in gingival crevicular fluid (GCF) after orthodontic force application. The choice of orthodontic devices, such as self-ligating brackets, also affects cytokine concentrations. The review discusses the impact of cytokines on orthodontic tooth movement (OTM), including the inflammatory response, bone remodeling, and soft tissue changes. It also examines the influence of cytokines on mini-implant stability and the inflammatory response in patients with chronic diseases like type 2 diabetes mellitus (T2DM). The study concludes that understanding the biological mechanisms of cytokines is essential for optimizing orthodontic practices and patient care, suggesting that further research is needed to enhance clinical outcomes and reduce treatment times.This systematic review by Inchingolo et al. explores the intricate relationship between cytokines and orthodontic treatment (OT). Cytokines, low-molecular-weight proteins involved in immune responses, play a crucial role in both innate and acquired immune responses. The review highlights the multifaceted role of cytokines in OT, emphasizing how orthodontic forces induce tension and compression in the periodontal ligament (PDL), leading to the release of cytokines. Proinflammatory cytokines, such as IL-1, IL-6, and TNF, influence bone and soft tissue metabolism, with elevated levels observed in gingival crevicular fluid (GCF) after orthodontic force application. The choice of orthodontic devices, such as self-ligating brackets, also affects cytokine concentrations. The review discusses the impact of cytokines on orthodontic tooth movement (OTM), including the inflammatory response, bone remodeling, and soft tissue changes. It also examines the influence of cytokines on mini-implant stability and the inflammatory response in patients with chronic diseases like type 2 diabetes mellitus (T2DM). The study concludes that understanding the biological mechanisms of cytokines is essential for optimizing orthodontic practices and patient care, suggesting that further research is needed to enhance clinical outcomes and reduce treatment times.