In 2004 we first reported catalytic nanoparticles, that are able to cleave phosphate diesters with very high efficiency (Angew. Chem. Int Ed, 2004, 43, 6165–6169) and dubbed them “nanozymes” for the similarity of their behavior with natural enzymes, both in terms of efficiency and mechanism of action. Since then the field has impressively expanded and a search on the web of science at the time of submitting this contribution returned almost 1,000 entries. This minireview highlights what has been done in the field focusing specifically on hydrolytic nanozymes, the focal point of the research in our group since its very beginning. Special emphasis is given to the advantage of bringing catalytic units in the confined space of a nanosystem in terms of inducing the cooperation between them, favoring the interaction with substrates, and altering the local environment. We will try to answer to questions like: why can a lipophilic substrate be transformed by these catalysts even in an aqueous environment? Why may the pH in the catalytic loci of the nanosystem be different from that of the bulk solution even in the presence of buffers? Why are most of these nanosystems better than monovalent ones?