The assembly of proteins into various types of aggregates is a central event in a variety of biological and industrial processes that can be detrimental (e.g., neurological disease, inactivation of protein therapeutics) and, in some cases, beneficial (e.g., prion regulation of long-term memory). The complex molecular interactions that guide the assembly of many protein aggregates are poorly understood since they are difficult to characterize experimentally, a problem that stems primarily from the wide array of time-dependent conformational and oligomeric states sampled by these proteins. We have sought to develop a new experimental framework for dissecting the molecular basis of how aggregation-prone proteins both self- and cross-associate by studying their interaction with arrays of surface-bound peptides. We have applied this methodology to study physical interactions between naturally occurring variants of the yeast prion protein, Sup35p, that in vivo are either soluble or aggregated depending on the prion state. Our primary interest is to define the physical basis for the relative ability of various prion aggregates to transmit their β-sheet rich conformational states to other proteins, which is important in several biological processes and has received much attention due to the public health risk of transmitting mammalian prion conformers from cattle and deer to humans. In this presentation we will discuss the use of peptide arrays to identify critical interaction sites within the sequences of several prion proteins and show that the specificity of these interaction sites, which can be modulated by mutations and/or environmental conditions, governs the relative transmission of conformational states between these proteins. We will also discuss the extension of our methods of characterizing interactions between misfolded proteins to investigate other important biological problems.