One of the major challenges in studying brain function and diseaseslies in the difficulty in deliveringmoleculesto the brain due to the presence of the blood-brain barrier (BBB). This project is aimed at developing a novel and effective method to deliver molecules to the brain for analyzing the molecular and cellular levels of brain functions in normal and brain-diseased animals (Alzheimer’s, multiple sclerosis, and brain tumors animal models). The central hypothesis is thatcadherin peptides(HAV and ADT) modulate cell-cell adhesion in the intercellular junctions of the BBB to enhance paracellular permeation of small-to-large molecules through the BBB. The results showed that cadherin peptidesincrease the in vivo brain delivery of drugs (camptothecin), paracellular marker molecules (C-mannitol, gadopentetic acid), H-PEG, and 25 kDa IRdye800cw-PEG), efflux pump substrates (rhodamine 800 (R800), H-daunomycin), 8–12 amino acid peptides (i.e., cIBR7 and cLABL), and proteins (i.e., 65 kDa galbumin) in mice and rats. These results strongly support the possibility of using cadherin peptides for non-invasive delivery of various molecules for diagnostic or therapeutic purposes to the brains of brain diseased animal models.The HAV and ADT peptides are non-toxic, and they can safely modulate the BBB for a short period to allow BBB penetration of large proteins. We also found that ADT and HAV peptides bind to the EC1 domain of E-cadherin at different binding sites.In summary,our work is the first to show that modulating cell-cell adhesion can safely increase the delivery of molecules to the brain in living mice and rats. The concept of modulating cell-cell adhesion of the BBB to improve delivery of molecules to the brain is novel and would have a broad impact on the diagnosis and treatment of brain diseases.