Transition metals have been used to mediate bioorthogonal reactions within a biological environment. In particular, applications of biocompatible palladium catalysis currently range from biomolecules modification to the in cellulo synthesis or activation of drugs. Here, the scope of palladium-mediated chemistry in living systems has been further extended with the development of a new homogenous palladium catalyst. This water-soluble, biocompatible, and traceable catalysts is based on a palladium-carbene complex coupled to a fluorescent labelled homing peptide for targeted delivery inside cells. This “SMART” catalyst is designed to activate both caged fluorophores and drugs through the cleavage of protecting groups or cross-coupling reactions. A second strategy for targeted delivery of a biocompatible palladium catalysis involves metal nanoparticles loaded onto a heterogeneous solid support. This “modular” catalyst can be implanted in vivo at the desired site of action, e.g. a tumour, and locally activate biomolecules. These two catalytic systems will allow us to selectively activate pro-drugs in vivo, with spatial control, thus minimising the side effects of the treatment on the whole body.