Since its inception, the field of metabolic engineering has endeavored to engineer microbial cells by manipulating the canonical architecture of metabolism, which often entails concurrent engineering of substrate utilization, central metabolism, and product synthesis pathways. This inevitably creates interdependency with native metabolism leading to problematic crosstalk between product-forming and growth-sustaining functions that compete for the same carbon and energy carriers. Our laboratory has been addressing these shortcomings by engineering metabolic pathways that are orthogonal to the host metabolism and hence have the potential to operate efficiently, are amenable to different hosts, and can be deployed as both in vitro and in vivo platforms. Our efforts in this area started with the engineering of an iterative pathway for the efficient synthesis of longer-chain alcohols and carboxylic acids (Nature, 476:355-359, 2011), which we termed the b-oxidation reversal (r-BOX). We have further engineered the r-BOX to improve its orthogonality and achieve the synthesis of a host of functionalized small molecules at high carbon and energy efficiency (Nature Biotechnol, 34:556-561, 2016). Building on these successes, we have recently created new-to-nature pathways for the synthesis of isoprenoids (PNAS, 116:12810- 12815, 2019) and polyketides (Nature Catalysis 3, 593-603, 2020), as well as the bioconversion of one-carbon substrates (Nature Metabolism 3, 2021 DOI: 10.1038/s42255-021-00453-0; Nature Chem Biol, 15:900-906, 2019). In this talk, I will discuss challenges and opportunities in the development of orthogonal metabolic platforms to efficiently biomanufacture small organic molecules for chemical and pharmaceutical applications.