Colicins are water soluble toxins secreted by E. coli cells to kill other E. coli and related species. To do this they need to cross the outer membrane, periplasm and inner membrane. Pore forming colicins, as their name suggests form a voltage dependent pore in the inner membrane. This chapter deals with the interfaces, both lipid and protein, that the colicins experience as they make the short but complex journey that brings them to the point of pore formation. The succession of molecular interactions with lipid and protein receptors causes a series of conformational changes which allow these large > 40 kDa proteins to outwit the normally tight defensive shield of the target cell. This is done by combining general physico-chemical interfacial interactions, such as the use of amphipathic helical peptides, with precisely targeted protein-protein interactions involving both rigid and natively disordered protein domains.