Metabolic engineering, a field centered on redirecting metabolic pathways through geneticmanipulation, has significantly impacted drug discovery and development. This review delvesinto recent advancements where genetic engineering and biosynthetic chemistry intersect,particularly focusing on their influence on natural-product drug discovery. Natural products,comprising a substantial percentage of successful drugs, possess therapeutic properties butoften present challenges in terms of optimization of pharmacokinetics, production costs, andyields from their native hosts. Organic chemistry methodologies and combinatorial synthesishave been instrumental in enhancing the pharmacological potential of these compounds,allowing for precise modifications and the creation of diverse molecular variations.Enzymes have emerged as crucial tools for in vitro combinatorial functionalization of complexmolecules, with potential applications in cell-based combinatorial synthesis. Leveragingheterologous hosts for producing drugs involves introducing genes in biosynthetic cascades,demanding careful gene balancing to avoid bottlenecks or overexpression that could hinderproduct synthesis. Balancing gene expression and metabolic flux within the heterologouspathways and the native host metabolism poses a core challenge in metabolic engineering fordrug production.Recent advancements in metabolic engineering have simplified the cloning and analysis ofbiosynthetic pathways, enhancing protein and metabolic engineering programs. Theconvergence of genetic engineering and biosynthetic chemistry offers promising avenues forcost-effective drug production, especially pertinent for treating diseases in developing nationswhere drug costs often limit accessibility. By highlighting the impact of metabolic engineering onnatural-product drug discovery, this review emphasizes the potential for introducing a multitudeof drug candidates into the pipeline, thereby addressing the challenges of low success rates, longdevelopment times, and high costs associated with drug development.