Neuropsychiatric systemic lupus erythematosus (NPSLE) is one of the most severe manifestations of SLE with a heterogeneous clinical presentation comprising 19 syndromes. Current prospective studies show that approximately 56% of patients with SLE have a neuropsychiatric event, 30–50% of which are directly caused by the pathogenic mechanisms of SLE. Pathogenesis begins with a breach in the blood-brain barrier, which allows the entry of peripheral autoimmune mediators such as anti-NMDAR and anti-ribosomal P antibodies, type I IFN, IL-6, and NET-forming neutrophils into the CNS. In the CNS, microglia become polarized to a pro-inflammatory M1 phenotype and astrocytes to a neurotoxic A1, leading to neuroinflammation and pathological synaptic stripping. The adaptive immune system includes infiltration of T cells such as Tfh in the choroid plexus and Eomes+ double-negative T cells in the brain parenchyma, as well as local production of autoantibodies by B-cells. Single-cell genomics and spatial transcriptomics reveal cellular heterogeneity from models such as MRL/lpr and NZB/W F1. These insights allow stratification into immune endophenotypes for biomarkers such as NfL, GFAP, CXCL13 and targeted therapies such as IFN receptor blockade.