Amyloidosis has a special place in the history of medicine, involving numerous physicians and researchers from multiple disciplines throughout the medical field due to its initial enigmatic nature and systemic involvement. Many developments occurred during the last 2 centuries, hand in hand with advancements in the understanding of protein synthesis and folding, metachromatic staining, polarized microscopy, amyloid extraction, electrophoresis, electron microscopy, and genomics. Amyloidosis is basically a disorder of protein misfolding, forming beta sheets which in turn compose protofilaments winding around each other to form the amyloid fibril. Amyloidosis occurs when amyloid fibrils form aggregates and deposit in various tissues, causing organ dysfunction. In some instances, the circulating amyloid precursor oligomers also exert a toxic effect. The current classification of amyloidosis is based upon the precursor misfolded proteins. The two most common forms that cause cardiac amyloidosis are AL and ATTR amyloidosis. AL amyloidosis occurs when excessive amyloidogenic light chains are produced by plasma cells. ATTR amyloidosis is the result of either mutant transthyretin misfolding (ATTRv) or wild type transthyretin (ATTRwt). Age related protein oxidative modifications and failure of proteostasis and repair mechanisms contribute to the dissociation and aggregation of normal TTR (wild type) into amyloid fibrils. Similar to light chains, the misfolded TTR monomers and dimers also have a toxic cardiac effect. Cardiac amyloid deposition results in myocardial diastolic and systolic dysfunction. Furthermore, amyloid also involves the cardiac valves, the conduction system, coronary arteries and even the pericardium. If untreated, patients develop heart failure and eventually cardiogenic shock and death due to the very limited stroke volume in advanced cardiac amyloidosis. Currently, diagnosis and therapy for both forms of amyloid have drastically improved due to a better understanding of light chain and ATTR pathogenesis. The non-biopsy diagnostic algorithm incorporating free light chain measurement and scintigraphy allowed for improved recognition of ATTR amyloidosis in the elderly and heart failure population. Endomyocardial biopsy and genetic testing are warranted in order to diagnose the less frequent forms of amyloidosis (AA in inflammation, Abeta-2 microglobulin in long term dialysis, and the rare ApoA-I, ApoA-II, ApoA-IV, and Agel amyloidosis).