Bioorthogonal nanocatalysts in the form of 'nanozymes', are promising tools for generating imaging and therapeutic molecules in living systems. These systems use transformations developed by synthetic chemists to effect transformations that cannot be performed by cellular machinery. This emerging platform is rapidly evolving towards the creation of smart nanodevices featuring the capabilities of their enzyme prototypes, modulating catalytic activity through structure as well as chemical and physical signals. Here we describe different strategies to fabricate these nanocatalysts and their potential in diagnostic and therapeutic applications.