Routine calcitonin assay programs and recent studies on the natural history of familial medullary thyroid carcinoma (MTC) have greatly added to our understanding of C-cell hyperplasia (CCH) and refined its classification. This article is an update on CCH physiopathology related to clinical presentation. With this combined approach, two types of CCH that differ by their physiological characteristics can be identified: neoplastic CCH and reactive (also called physiological) CCH. Neoplastic CCH is caused by a germline mutation of the RET protooncogene in a multiple endocrine neoplasia type 2 (MEN 2) syndrome. It progresses to MTC following a time line that depends on the RET mutation involved. CCH may actually be a misnomer for a neoplastic condition that some authors have proposed to call "in situ-MTC". Reactive CCH is considered to be caused by a stimulus that is external to the C-cell, and its premalignant potential is not documented. Many situations such as hypercalcemia, hyperparathyroidy, chronic lymphocytic thyroiditis or follicular tumors have been associated with reactive CCH, the pathogenesis of which remains unclear. But C-cell density in normal patients is subject to important variability, and several studies have demonstrated the dramatic male predominance in physiological CCH when hypercalcitoninemia was a random discovery. These data suggest that a number of conditions which were previously associated with reactive CCH might be purely fortuitous. Our clinical/pathological confrontation contributes to appropriately distinguishing between various CCH types, and in turn to identify the best way of managing patients.