One of our major goals is to elucidate and highlight the unexpected outcomes that result from modifying living systems and formalize them under the umbrella of “incompatibilities”. For example, when multiple recombinant proteins are co-expressed in bacteria like E. coli, the cellular growth rate reduces, due to the burden of protein expression. However, the same system can be considered as an incompatibility between the resources used for protein synthesis and the bacterial host’s intrinsic resource demands for growth. Similarly, when a recombinant enzyme is expressed in a recombinant host, its off-target activity on host metabolites can result in re-distribution of fluxes through a number of host metabolic pathways. While such activity is frequently filed under promiscuousenzymatic activity, the same can be considered an incompatibility between the enzyme and the host’s metabolic network. We have spent significant effort in systematically exploring the origin these numerous host-part incompatibilities (where, the added component, like recombinant protein, is referred to as a biological “part”) in efforts to explain previously inexplicable experimental observations. By understanding the origins of incompatibilities, our work has revealed fundamental insights into cellular physiology and enabled development of more robust and efficient engineered biological systems.