The amyloidoses comprise a group of disorders of diverse etiology, in which different proteins undergo abnormal folding, leading to their deposition in tissues and concomitant tissue toxicity. This process ultimately leads to tissue destruction, with organ failure and progressive disease. Recent progress in the treatment of the systemic amyloidoses has dramatically changed the outlook for affected patients and their families. From a relatively rare and esoteric disorder that was typically diagnosed only at autopsy, or was invariably fatal if diagnosed during life, it has now become a disease for which, with modern therapies, durable responses and long-term survival can be achieved. The clinical symptoms are largely nonspecific, and therefore misdiagnosis, or late diagnosis, have been major detriments in achieving better treatment outcomes. Despite advances in laboratory medicine, amyloidoses are still diagnosed on the basis of the pathologic detection of deposits in tissues. Thus, effective primary screening for these diseases requires the active engagement of the pathology community at large, while specialized laboratories and treatment centers can offer secondary consultation and assistance with further steps. This review provides an update on pathogenesis, the clinical and pathologic features, and treatments of various amyloidoses, as well as the current terminology, classification, and practical considerations that are relevant to the diagnosis.