The production of chemicals, biologics, and therapeutics on an industrial scale increasingly uses simple microorganisms and complicated mammalian systems. Natural strains often generate limited and economically unviable quantities of the desired bioproduct and present physiological, experimental, and operational challenges when used at industrial scales. Therefore, systematically improving these biological systems is essential to smooth a bioprocess and maximize operation economics. This results-oriented approach towards enhancing industrially important producers’ genetic and physical characteristics is called strain improvement. The workflow has traditionally employed classical mutagenesis approaches, followed by screening and selecting enhanced mutants. With modern genetic, recombinant, and system biology tools, targeted modifications to the desired genes or whole pathway adjustments have become possible. Additionally, the ability to precisely and parallelly engineer genomes at single residue levels have increased the overall throughput of the strain improvement process. Here, the authors survey various classical to modern approaches to strain improvement and their collective implications for bioprocess engineering.