This article summarizes the major clinical, pathological, and molecular features of medullary thyroid carcinoma (MTC), based on a review of the most significant advances in our understanding of this tumor type over the last 25 years. MTC is a neuroendocrine carcinoma that shows evidence of C-cell differentiation. The tumor has a distinctive morphologic appearance, including the presence of amyloid deposits. Immunostaining for calcitonin, carcinoembryonic antigen, calcitonin gene-related peptide, and thyroid transcription factor 1 is helpful in differential diagnosis. Identification of RET mutations in familial and sporadic MTC has brought important changes in early diagnosis and treatment. Surgery remains the cornerstone of effective therapy. Understanding the molecular basis of MTC will allow identification of novel approaches for individualized treatment.