Substance-related disorders ( SRDs) are a series of physical and mental disorders, involving drug abuse, medicinal side effects, and toxin exposure. SRDs, including alcohol- and drug-related disorders, have become a serious worldwide public health problem. Methyl-CpG-binding protein 2 (MeCP2), an important regulator in the central nervous system, has an important role in many biological functions, such as synaptic plasticity, neuron development, and adult brain function. Many studies have shown that MeCP2 is involved in several SRDs. MeCP2 exerts its regulatory effects on the transcription of genes leading to changes in hormone levels, inflammation, and synaptic plasticity. Generally, MeCP2 influences reward behavior, social behavior, cognitive behavior, and spatial memory. The regulatory mechanism of MeCP2 on SRDs is complex and is poorly understood. Here, we review the role of MeCP2 in SRDs, which will aid future studies of SRDs.