Rett syndrome (RTT) and MECP2 duplication syndrome (MDS), which are categorized as MECP2-related disorders, are severe neurodevelopmental conditions caused by mutations or abnormalities in the dosage of the MECP2 gene. These diseases share the common clinical features of severe intellectual disability and motor developmental deficits and are characterized by diverse cellular and molecular phenotypes, including synaptic dysfunction and abnormal neuronal growth. Advances in stem cell research, particularly the emergence of induced pluripotent stem cell (iPSC) technology, have provided groundbreaking tools for investigating these diseases. Patient-derived disease-specific iPSCs for MECP2-related disorders have become indispensable for modeling disease phenotypes and exploring therapeutic strategies. Two-dimensional (2D) neuronal culture systems using iPSCs enable the study of disease-specific neuronal characteristics and synaptic abnormalities, offering critical insights into the cellular and molecular underpinnings of RTT and MDS. Furthermore, the development of a culture system for three-dimensional (3D) iPSC-derived brain organoids has made it possible to mimic the complex architecture and developmental processes of the human brain and better understand the neurodevelopmental aspects of MECP2-related diseases. The integration of iPSC-based modeling systems with multi-omics technologies has accelerated the identification of disease mechanisms and therapeutic targets. These innovative methodologies have also enabled the evaluation of novel compounds for the treatment of these diseases and the implementation of personalized treatment strategies to bridge the gap between basic research and clinical applications. This chapter highlights the transformative role of stem cell research in elucidating the pathophysiology of MECP2-related disorders and in developing therapeutic avenues for these diseases. In this section, we outline how the use of stem cell-based model systems has greatly advanced our understanding of the pathophysiologies underlying RTT and MDS, thus paving the way for the development of novel therapeutic approaches.