Gastrointestinal stromal tumors (GISTs) are a rare but increasingly common type of sarcoma that occurs along the digestive tract. More than 75% of GISTs arise in the stomach or small intestine, but tumors can arise anywhere along the GI tract and, in rare cases, within the abdominal cavity. Management varies based on several factors including tumor size, location, and mitotic rate, as well as mutational analysis. Treatment typically involves surgery, with many small GISTs being curable with surgery alone, and targeted therapies such as tyrosine kinase inhibitors (TKIs), which particularly benefit patients with large bulky tumors or distant disease. Prior to the development of targeted therapies, metastatic GISTs were associated with poor prognosis due to these tumors’ inherent resistance to chemotherapy and radiation treatment. However, the advent of TKIs has dramatically improved survival. The most used TKI is imatinib, which is the standard first-line of treatment and generally the best tolerated among patients. In cases where imatinib is not effective, there are several other newly developed TKIs available for treatment, and research is actively ongoing to develop new targeted agents. The development of novel targeted treatment options will be especially helpful for the management of GISTs in rare anatomical sites and with TKI resistance.