Microbe-mediated chemical production can replace traditional fossil-dependent production and hereby ensure sustainable production of chemicals that are important for our society. Significant success in economical chemical bioproduction has been accomplished by improving the cellular properties of microbial cells through metabolic engineering. The emergence of new techniques and strategies has led to a significant reduction in the turnaround time in the classic design-build-test-learn (DBTL) cycle in metabolic engineering. Here, we summarize the recent achievements and trends in microbial production of chemicals, with a focus on biofuels and high-value natural compounds. In addition, we offer perspectives on the challenges and opportunities for the successful establishment of future microbial chemical factories.