The importance of protein-protein interaction in the control of physiological functions has become increasingly evident. The ability of studying these interactions in the environment where they normally occur, the living animal, represents a major challenge. Here we took advantage of a recently developed biophysical approach known as bioluminescence resonance energy transfer (BRET) to assess molecular interaction “in vivo”. BRET is non-radiative transfer of energy between an energy donor (luciferase) and an energy acceptor (green fluorescent protein (GFP)). The energy transfer occurs only if the luciferase and the GFP are within 100 Å from each other and is dependent of the distance separating them. Combined with the use of fusion between the proteins of interest and both luciferase and GFP, BRET allows the real-time monitoring of protein-protein interactions. This method has successfully been used in various cell culture systems including bacteria and mammalian cell lines. The aim of this study is to determine if BRET can be used to monitor cellular activities and protein-protein interactions in living animals. To do so, two transgenic mice models were generated. The first one expresses an apoptosis sensor transgene which results from the covalent fusion of renilla luciferase (Rluc) to a GFP through a linker region containing a caspase-3 cleavage site. Upon apoptosis induction and caspase-3 activation, the fusion protein should be cleaved, resulting in a decrease in the BRET signal. The second mice model was designed to monitor the recrutement of the accessory protein barrestin to the b2-adrenergic receptor (b2AR) upon receptor activation. For this purpose, transgenic mice lines ubiquitously expressing barrestin fused to GFP and b2AR fused to Rluc were generated. In both cases, the animals were found to be viable and to express the appropriate constructs. BRET signal was detected in cells derived form the mice expressing the apoptosis sensor and caspase-3 activation leads to a decrease in the signal. The animals co-expressing barrestin-GFP and b2AR-Rluc are currently being investigated. These studies should provide a proof of principle that BRET can be used to monitor protein-protein interaction in living animals.