Janus kinase (JAK) inhibitors, including tofacitinib, baricitinib, upadacitinib and filgotinib, are increasingly used in the treatment of rheumatoid arthritis (RA). There has been debate about their safety, particularly following the issuance of guidance by regulatory agencies advising caution in their use in certain patients. The registrational clinical trials and registry data of JAK inhibitors did not identify a difference in therisk of major adverse cardiovascular events (MACEs), venous thromboembolism, malignancies or infections (other than herpes zoster) with a JAK inhibitor versus abiologicDMARD. In the ORAL Surveillance trial, which enrolled patients >50 yearsof age with ≥1 cardiovascular risk factor, tofacitinib was statistically inferior to TNF inhibitors for the occurrence of MACEs and malignancy. Further post hoc analysis of the data revealed that anageof ≥65 years, ahigh baseline cardiovascular risk, ahistory of smoking, sustained inflammation, disease activity and suboptimal treatment of cardiovascular comorbidities all increase the risk of these outcomes. The guidance issued by regulatory agencies should be carefully considered to ensure appropriate and safe treatment of patients with RA without undertreatment of patients who might benefit from JAK inhibitor, as well as biologic, treatment. As always, the risks associated with the use of these agents, treatment goals, costs and patient preferences should be discussed with the patient.