Hydroxychloroquine and chloroquine, antimalarial drugs, are widely used in the treatment of rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and other inflammatory rheumatic diseases. Despite their extensive clinical use, the mechanisms of action of these drugs are still emerging. These drugs are weak bases with a large volume of distribution and a long half-life. They interfere with lysosomal activity and autophagy, interact with membrane stability, and alter signaling pathways and transcriptional activity, leading to inhibition of cytokine production and modulation of co-stimulatory molecules. These mechanisms, combined with their chemical properties, explain their clinical efficacy and adverse effects, such as retinopathy. However, the dose–response relationships and the lack of defined minimum doses for clinical efficacy pose challenges in clinical practice. Patient non-adherence and variations in blood drug levels also complicate their use. Further research is needed to understand the immunomodulatory potency of these drugs and to develop more potent and selective inhibitors. The review discusses the pharmacokinetic and pharmacodynamic properties of hydroxychloroquine and chloroquine, including their absorption, distribution, elimination, and drug interactions, to better understand their clinical efficacy and safety.Hydroxychloroquine and chloroquine, antimalarial drugs, are widely used in the treatment of rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and other inflammatory rheumatic diseases. Despite their extensive clinical use, the mechanisms of action of these drugs are still emerging. These drugs are weak bases with a large volume of distribution and a long half-life. They interfere with lysosomal activity and autophagy, interact with membrane stability, and alter signaling pathways and transcriptional activity, leading to inhibition of cytokine production and modulation of co-stimulatory molecules. These mechanisms, combined with their chemical properties, explain their clinical efficacy and adverse effects, such as retinopathy. However, the dose–response relationships and the lack of defined minimum doses for clinical efficacy pose challenges in clinical practice. Patient non-adherence and variations in blood drug levels also complicate their use. Further research is needed to understand the immunomodulatory potency of these drugs and to develop more potent and selective inhibitors. The review discusses the pharmacokinetic and pharmacodynamic properties of hydroxychloroquine and chloroquine, including their absorption, distribution, elimination, and drug interactions, to better understand their clinical efficacy and safety.