Amyloidosis is a group of conditions defined by extracellular deposition of insoluble proteins that can lead to multiorgan dysfunction and failure. The systemic form of the disease is often associated with a plasma cell dyscrasia but may also occur in the setting of chronic inflammation, long-term dialysis, malignancy, or multiple hereditary conditions. Localized forms of the disease most often involve the skin, tracheobronchial tree, and urinary tract and typically require tissue sampling for diagnosis, as they may mimic many conditions including malignancy at imaging alone. Advancements in MRI and nuclear medicine have provided greater specificity for the diagnosis of amyloidosis involving the central nervous system and heart, potentially obviating the need for biopsy of the affected organ in certain circumstances. Specifically, a combination of characteristic findings at noninvasive cardiac MRI and skeletal scintigraphy in patients without an underlying plasma cell dyscrasia is diagnostic for cardiac transthyretin amyloidosis. Histologically, the presence of amyloid is denoted by staining with Congo red and a characteristic apple green birefringence under polarized light microscopy. The imaging features of amyloid vary across each organ system but share some common patterns, such as soft-tissue infiltration and calcification, that may suggest the diagnosis in the appropriate clinical context. The availability of novel therapeutics that target amyloid protein fibrils such as transthyretin highlights the importance of early diagnosis.