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Immune checkpoint (IC) pathways, originally identified in T-cell exhaustion in cancer, are increasingly recognized as key modulators of immune tolerance in autoimmune diseases (ADs). In ADs, these molecules function more accurately as inhibitory receptors (IRs) that fine-tune, rather than inducing classical exhaustion phenotypes, autoreactive immune cells. Unlike oncology, where checkpoint blockade enhances immunity, AD therapy aims to restore tolerance through IC agonism or immune reset approaches (e.g., CAR-T cells). This review synthesizes recent advances in targeting CTLA-4, PD-1, LAG-3, TIM-3, and TIGIT. Clinical success with CTLA-4-Ig (abatacept) and emerging efficacy of PD-1 agonists (e.g., peresolimab) provide proof-of-concept that augmenting inhibitory signaling can ameliorate autoimmunity. However, outcomes remain context-dependent, reflecting interplay between effector and regulatory subsets and tissue-specific environments. Mechanistic challenges, including multivalent receptor engagement, ligand complexity, and signaling heterogeneity (e.g., ITIM/ITSM phosphorylation), limit current approaches. Insights from immune-related adverse events (irAEs) highlight shared pathways of dysregulation and inform risk-benefit considerations. A major translational gap persists between acute transplant models and chronic autoimmunity, and validated predictive biomarkers are lacking. Beyond T cells, B cells, dendritic cells, and innate populations expand therapeutic opportunities. Future progress will require multi-omics profiling, biomarker-driven stratification, and next-generation agonist design. IC-targeted strategies hold promises but demand context-aware, mechanistically informed development for broad clinical impact in ADs.