Amyloidosis associated with immunoglobulin M clones is a distinct clinical entity that poses specific challenges to clinicians. Although there is substantial overlap, the pattern of organ involvement is peculiar, with higher frequencies of lung, lymph nodes, and peripheral nervous system involvement. Early diagnosis is vital to start effective therapy before irreversible organ damage has occurred and should be based on markers of initial, asymptomatic organ dysfunction, such as natriuretic peptides for heart involvement and albuminuria for renal amyloidosis. Immunoglobulin M clones can give rise to both light chain (AL) and reactive (AA) amyloidosis, and once the diagnosis of amyloidosis is made, correct amyloid typing is necessary to design appropriate therapy and follow-up. Prognostic stratification should include serum albumin concentration, which is an independent prognostic factor.