Rheumatologic ailments are often characterized by inflammation involving joints, soft tissue (ie muscle) and vasculature. In order to combat the symptoms associated with rheumatologic disease, which are often pain and inflammation related, certain classes of medications are typically utilized–these include but are not limited to: oral analgesics, nonsteroidal anti-inflammatory drugs, steroids, muscle relaxants, herbal supplements, sulfasalazine, leflunomide and other non-biologic therapies which will be this chapter’s focus. Gastrointestinal side effects are an unfortunate reality with many of the prescribed medications in rheumatologic disease; this often requires the clinician to assess a fine balance of risk and benefit in the individualized treatment approach to the patient. Side effects can be as benign as simple abdominal discomfort to as drastic as complete fulminant hepatic failure. This chapter will focus on gastrointestinal side effects of frequently prescribed non-biologic medications as well as several lesser known treatments that are used to address rheumatologic disease.