Evaluation of acute right lower quadrant pain remains a common and challenging clinical scenario for emergency medicine physicians due to frequent nonspecific signs, symptoms, and physical examination findings. Therefore, imaging has evolved to play a pivotal role in the emergency setting. While appendicitis is a common cause for acute pain, there are numerous other important differential considerations with which the radiologist must be aware. The purpose of this review is to list an anatomy-based, encompassing differential diagnosis in addition to acute appendicitis for right lower quadrant pain; demonstrate the key imaging findings of numerous differential considerations; and describe helpful imaging and clinical features useful in narrowing the differential diagnosis.