In the past decade, single-cell technologies have proliferated and improved from their technically challenging beginnings to become common laboratory methods capable of determining the expression of thousands of genes in thousands of cells simultaneously. The field has progressed by taking the CNS as a primary research subject — the cellular complexity and multiplicity of neuronal cell types provide fertile ground for the increasing power of single-cell methods. Current single-cell RNA sequencing methods can quantify gene expression with sufficient accuracy to finely resolve even subtle differences between cell types and states, thus providing a great tool for studying the molecular and cellular repertoire of the CNS and its disorders. However, single-cell RNA sequencing requires the dissociation of tissue samples, which means that the interrelationships between cells are lost. Spatial transcriptomic methods bypass tissue dissociation and retain this spatial information, thereby allowing gene expression to be assessed across thousands of cells within the context of tissue structural organization. Here, we discuss how single-cell and spatially resolved transcriptomics have been contributing to unravelling the pathomechanisms underlying brain disorders. We focus on three areas where we feel these new technologies have provided particularly useful insights: selective neuronal vulnerability, neuroimmune dysfunction and cell-type-specific treatment response. We also discuss the limitations and future directions of single-cell and spatial RNA sequencing technologies. In this Review, the authors discuss the ways in which single-cell and spatially resolved transcriptomics are contributing to our understanding of the pathophysiology of neurological conditions. They also discuss the limitations and possible future directions of these technologies. Key points: High-throughput single-cell technologies enable multiple layers of molecular biology to be probed at the single-cell level. Single-cell transcriptomic atlases spanning multiple developmental stages have been generated with the aim of dissecting the cellular complexity of the human brain. Single-cell RNA sequencing technologies increase our understanding of pathomechanisms of brain disorders, providing information on selective neuronal vulnerability, neuroimmune aspects and cell-type-specific treatment responses. Spatially resolved transcriptomics provides information about the relationships between spatial tissue organization and dysregulated molecular networks in the vicinity of pathogenic hallmarks. Single-cell transcriptomic methods have proven useful in the biomedical field and are emerging as valuable future tools for diagnostics and the development of precision treatments in clinical practice. [ABSTRACT FROM AUTHOR]