Hydroxychloroquine and chloroquine are weak bases with a large volume of distribution and long half-lives, accumulating in acidic compartments like lysosomes and inflamed tissues. They inhibit lysosomal activity and autophagy, disrupt membrane stability, and alter signaling pathways and transcription, leading to reduced cytokine production and modulation of co-stimulatory molecules. These mechanisms explain their immunomodulatory effects and adverse effects, such as retinopathy. Despite their clinical efficacy in rheumatic diseases like RA, SLE, and APS, challenges remain in defining optimal dosing, understanding dose-response relationships, and managing drug interactions. Hydroxychloroquine is effective in reducing disease flares and improving outcomes in SLE, but its efficacy in hand osteoarthritis is limited. It also has anti-inflammatory and antithrombotic effects, though its exact mechanisms are not fully understood. The drugs can interact with other medications, affecting their metabolism and concentrations. Hydroxychloroquine is generally safe but carries a risk of retinopathy, leading to updated ophthalmology guidelines recommending a maximum daily dose of 5.0 mg/kg. Current research focuses on elucidating their molecular targets, such as PPT1, and exploring their potential in treating autoimmune diseases. Despite their long-term use, the exact mechanisms of action remain under investigation, with ongoing studies aiming to improve therapeutic strategies and safety profiles.Hydroxychloroquine and chloroquine are weak bases with a large volume of distribution and long half-lives, accumulating in acidic compartments like lysosomes and inflamed tissues. They inhibit lysosomal activity and autophagy, disrupt membrane stability, and alter signaling pathways and transcription, leading to reduced cytokine production and modulation of co-stimulatory molecules. These mechanisms explain their immunomodulatory effects and adverse effects, such as retinopathy. Despite their clinical efficacy in rheumatic diseases like RA, SLE, and APS, challenges remain in defining optimal dosing, understanding dose-response relationships, and managing drug interactions. Hydroxychloroquine is effective in reducing disease flares and improving outcomes in SLE, but its efficacy in hand osteoarthritis is limited. It also has anti-inflammatory and antithrombotic effects, though its exact mechanisms are not fully understood. The drugs can interact with other medications, affecting their metabolism and concentrations. Hydroxychloroquine is generally safe but carries a risk of retinopathy, leading to updated ophthalmology guidelines recommending a maximum daily dose of 5.0 mg/kg. Current research focuses on elucidating their molecular targets, such as PPT1, and exploring their potential in treating autoimmune diseases. Despite their long-term use, the exact mechanisms of action remain under investigation, with ongoing studies aiming to improve therapeutic strategies and safety profiles.