Immunomodulatory therapy for rheumatoid arthritis (RA) carries risk for infectious complications. Understanding the risks of different therapeutic options is essential for making treatment decisions and appropriately monitoring patients. This review examines data on the risks for serious infections and other key infections of interest for the major classes of agents in use for RA: glucocorticoids, conventional synthetic disease-modifying antirheumatic drugs (DMARDs), biologics and Janus kinase (JAK) inhibitors. Conventional synthetic DMARDs have an excellent safety profile with recent data available supporting the relative safety of methotrexate. Tumour necrosis factor (TNF) inhibitors are associated with an increase in the risk of serious infections. Risk with other biological agents and with JAK inhibitors varies somewhat but overall appears similar to that of TNF inhibitors, with JAK inhibitors also associated with a greater risk of herpes zoster. Glucocorticoids have a dose-dependent effect on serious infection risk-at higher doses risk of infection with glucocorticoids is substantially greater than with other immunomodulatory therapies, and even low-dose therapy carries a risk of infection that appears to be similar to that of biological therapies.