Symmetric inflammatory polyarthritis is the most prominent manifestation of rheumatoid arthritis (RA). However, RA can practically affect any organ system, whether hematologic, neurological, cardiac, lung, skin, eyes, or kidneys. Systemic involvement in RA can be severe when there is interstitial lung disease, scleritis, amyloidosis, pure red cell aplasia, or myelodysplasia. Cardiovascular disease is the leading cause of death in patients with RA with a similar cardiovascular risk to that with diabetes mellitus. Patients with RA are at an increased risk of infections or osteoporosis, largely due to treatment-related etiologies. Rheumatoid vasculitis is a devastating long-term complication of RA which is fortunately becoming rarer over time due to better disease activity control. While the risk of mortality overall seems to be reducing over time, the excess mortality risk with RA compared with the general population persists. Fibromyalgia, anxiety, depression, fatigue, and physical inactivity remain important comorbidities associated with RA.