Hydroxychloroquine (HCQ), one of the oldest drugs used in rheumatology, came recently into attention as one of the potential therapies tested for the severe acute respiratory syndrome coronavirus-2 disease treatment. Used initially as an antimalarial, then translated to rheumatic diseases, HCQ has been used in a wide range of pathologies, including infectious diseases, immune disorders, diabetes, dyslipidemia, or neoplasia. Regarding systemic diseases, HCQ is the mainstay treatment for systemic lupus erythematosus (SLE), where according to last European guidelines is it proposed to all SLE patients unless contraindicated or with side effects. HCQ proved positive impact in SLE on robust outcomes such as accrual damage, disease activity and survival, but also pleiomorphic effects including decrease in the need for glucocorticoids, reduction in the risk of neonatal lupus, lower fasting glucose and protection against diabetes, thrombotic risk, dyslipidemia, infections, etc.. Moreover, HCQ can be used during pregnancy and breast-feeding. Besides SLE, the role for HCQ in the antiphospholipid syndrome and Sjögren’s disease is still under debate. On the contrary, recent advances showed only limited interest for rheumatoid arthritis, especially due the lack of structural damage prevention. There are still no strong data to sustain the HCQ use in other systemic diseases. In this review we summarized the utility and efficacy of HCQ in different clinical conditions relevant for rheumatology practice.