Selective manipulation of complex organic molecules such as biomass derived carbohydrates or natural products can be achieved through several catalyst design strategies. In the first part of my talk, I will discuss how a specifically tuned Lewis acid catalyst was harnessed to selectively cleave carbon-oxygen (C–O) bonds of complex biologically sourced carbohydrates to prepare reduced polyols – many of which were reported for the first time. Further elaboration and tuning of this method towards the selective modification of complex natural products demonstrated that even in the presence of a diverse set of functional groups, high levels of selectivity could be achieved to prepare multiple novel scaffolds from a single starting material. Striving for even greater control over site-selectivity required a different approach to catalyst design. In the second part of the talk I will focus on the combination of an organometallic catalyst with a supramolecular cage to perform selective hydrogenation of simple and complex substrates. By controlling the steric environment and non-covalent interactions of an organometallic catalyst encapsulated in a supramolecular host, selective hydrogenation of a single olefin in the presence of three activatable olefins was achieved demonstrating enzyme-like selectivity.