Although recognized for more than 150 years, acute acalculous cholecystitis (AAC) remains an elusive diagnosis. This is likely because of the complex clinical setting in which this entity develops, the lack of large prospective controlled trials that evaluate various diagnostic modalities, and thus dependence on a small data base for clinical decision making. AAC most often occurs in critically ill patients, especially related to trauma, surgery, shock, burns, sepsis, total parenteral nutrition, and/or prolonged fasting. Clinically, AAC is difficult to diagnose because the findings of right upper-quadrant pain, fever, leukocytosis, and abnormal liver tests are not specific. AAC is associated with a high mortality, but early diagnosis and intervention can change this. Early diagnosis is the crux of debate surrounding AAC, and it usually rests with imaging modalities. There are no specific criteria to diagnose AAC. Therefore, this review discusses the imaging methods most likely to arrive at an early and accurate diagnosis despite the complexities of the radiologic modalities. A pragmatic approach is vital. A timely diagnosis will depend on a high index of suspicion in the appropriate patient, and the combined results of clinical findings (admittedly nonspecific), plus properly interpreted imaging. Sonogram (often sequential) and hepatic iminodiacetic acid scans are the most reliable modalities for diagnosis. It is generally agreed that cholecystectomy is the definitive therapy for AAC. However, at times a diagnostic/therapeutic drainage via interventional radiology/surgery may be necessary and life-saving, and may be the only treatment needed.