The Gram-positive bacterium B. thuringiensis (Bt) produces during sporulation a-PFTs insecticidal Cry proteins that bind specific receptor molecules on the brush border membrane of the insect midgut cells. Bt toxin-receptor interaction is widely accepted as a crucial step for toxicity and determines insect specificity. Bt Cry3Aa toxin is highly active against larvae of Colorado potato beetle (CPB), the most devastating insect pest of potatoes worldwide, but the receptor molecules involved in the Cry3Aa toxic action have not been identified yet. In this work, we searched in the CPB transcriptome (Kumar et al., 2014) and in the CPB genome that is currently being annotated (i5k-pilot-project), the homologous gene sequences encoding Bt toxin functional receptors in the coleopteran model insect Tribolium castaneum, cadherin-like and sodium solute symporter proteins. We also searched for the CPB ADAM10 metalloprotease gene sequence that we previously proposed encodes a Cry3Aa toxin receptor in CPB larvae (Ochoa-Campuzano et al., 2007). Next, we assessed the functional role of these three molecules as Cry3Aa toxin receptors in CPB larvae by RNAi gene silencing. Results demonstrated that CPB-ADAM10 protein is a Cry3Aa functional receptor in CPB. And finally, we investigated the relevance in Cry3Aa toxin mode of action of the proteolytic processing by digestive midgut juice proteases and by ADAM10 membrane associated metalloprotease in the context of the general mechanism of PFTs pathogenesis.