Peptide mediated gain-of-toxic function is central to pathology in diseases such as Alzheimer's and diabetes. Cytotoxicity has long been correlated with self-assembly of the peptides into membrane-associated oligomers. The relationship of such species to membrane poration and the nature of poration's effects on toxicity remain elusive. Here, we focus on islet amyloid polypeptide (IAPP), a hormone associated with β-cell loss in diabetics. Newly developed membrane leakage and diluted-FRET methods enable structure-function inquiry to focus on large N, homooligomers. Our results not only show the coexistence of two mechanisms of poration, but reveal that only one is cytotoxic. At no point do the porating conformations of IAPP match those of aqueous prepared amyloid. Membrane associated oligomers are internally dynamic and grow in discrete steps consistent with liquid-like fusion. Toxic permeation can be localized to mitochondria using a structure specific-ligand, illuminating a strategy for small molecule development applicable to partially ordered proteins.