Energy migration in self-assembled, water soluble, quantum dot (QD) nanoclusters is reported. These spherical nanoclusters are composed of CdSe QDs bound together by pepsin, a digestive enzyme found in mammals. A structural model for the clusters is suggested, based on scanning transmission electron microscopy, as well as dynamic light scattering and small angle X-ray scattering. Cluster sizes range from 100 to 400 nm in diameter and show a close-packed interior structure. Optical characterization of the absorption and emission spectra of the clusters is reported, finding photoluminescence quantum yields of up to approximately 60% in water for clusters made from core-shell CdSe–ZnS QDs. Clusters prepared from two different size populations of CdSe QD samples (3 and 4 nm in diameter) demonstrate energy migration and trapping. Resonance energy transfer (RET), from small to large dots within the QD–pepsin cluster, is observed by monitoring the quenching of the small donor dot fluorescence along with enhancement of the large acceptor dot fluorescence.