Cronkhite-Canada syndrome (CCS) is a rare, non-inherited polyposis syndrome, characterized by diffuse gastrointestinal (GI) hamartomatous polyposis with unique dermatologic changes including alopecia, skin hyperpigmentation, and nail dystrophy. Patients can typically present with diarrhea, weight loss, protein-losing enteropathy, and nutritional deficiency. However, it can demonstrate diverse other clinical features, usually with poor prognosis. Currently, there are no specific diagnostic criteria established yet. The etiology of CCS is still obscure, but an autoimmune process has been suggested. Here we present an 81-year-old Caucasian female who had clinical presentations, physical exam, imaging, endoscopy and pathology findings that were all consistent with the diagnosis of CCS. We also include a detailed literature review of the other gastrointestinal polyposis syndromes (hamartomatous, adenomatous, hyperplastic and inflammatory polyposis). A high index of suspicion and recognition of the characteristic clinical, endoscopic as well as histopathological findings of CCS, as well as different gastrointestinal polyposis conditions, can help clinicians with more timely and correct diagnosis.