Decades of research have been put in place for developing sustainable routes of bioproduction of high commercial value natural products (NPs) on the global market. In the last few years alone, we have witnessed significant advances in the biotechnological production of NPs. The development of new methodologies has resulted in a better understanding of the metabolic flux within the organisms, which have driven manipulations to improve production of the target product. This was further realised due to the recent advances in the omics technologies such as genomics, transcriptomics, proteomics, metabolomics and secretomics, as well as systems and synthetic biology. Additionally, the combined application of novel engineering strategies has made possible avenues for enhancing the yield of these products in an efficient and economical way. Invention of highthroughput technologies such as next generation sequencing (NGS) and toolkits for genome editing Clustered Regularly Interspaced Short Palindromic Repeats/CRISPR-associated 9 (CRISPR/Cas9) have been the game changers and provided unprecedented opportunities to generate rationally designed synthetic circuits which can produce complex molecules. This review covers recent advances in the engineering of various hosts for the production of bioactive NPs and biopharmaceuticals. It also highlights general approaches and strategies to improve their biosynthesis with higher yields in a perspective of plants and microbes (bacteria, yeast and filamentous fungi). Although there are numerous reviews covering this topic on a selected species at a time, our approach herein is to give a comprehensive understanding about state-of-art technologies in different platforms of organisms.