Microorganisms are remarkable producers of a wide diversity of natural products that significantly improve human health and well-being. Currently, these natural products comprise half of all the pharmaceuticals on the market. After the discovery of penicillin by Alexander Fleming 85 years ago, the search for and study of antibiotics began to gain relevance as drugs. Since then, antibiotics have played a valuable role in treating infectious diseases and have saved many human lives. New molecules with anticancer, hypocholesterolemic, and immunosuppressive activity have now been introduced to treat other relevant diseases. Smaller biotechnology companies and academic laboratories generate novel antibiotics and other secondary metabolites that big pharmaceutical companies no longer develop. The purpose of this review is to illustrate some of the recent developments and to show the potential that some modern technologies like metagenomics and genome mining offer for the discovery and development of new molecules, with different functions like therapeutic alternatives needed to overcome current severe problems, such as the SARS-CoV-2 pandemic, antibiotic resistance, and other emerging diseases. Key points • Novel alternatives for the treatment of infections caused by bacteria, fungi, and viruses. • Second wave of efforts of microbial origin against SARS-CoV-2 and related variants.• Microbial drugs used in clinical practice as hypocholesterolemic agents, immunosuppressants, and anticancer therapy. Keywords Microbial natural products • Antibiotics • Hypocholesterolemics• Anticancer drugs • Immunosuppressants • Antibiotic resistance Abbreviations FDA Food and Drug Administration NA Not applicable cSSSI Complicated skin, and skin structure infections ABSSSIs Acute bacterial skin, and skin structure infections cUTI Complicated urinary tract infections cIAI Complicated intra-abdominal infections HABP/VABP Hospital-acquired bacterial pneumonia, and ventilator-associated bacterial pneumonia CABP Community-acquired bacterial pneumonia. Estimate of U.S. Sales for 2018 was based on data previously reported Carr and Stringer 2019 * Sergio Sánchez