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This review describes the remarkable transition in the manufacture of β‐lactam antibiotics, which is driven by the desire to reduce or eliminate the production of waste and the dependence on organic solvents. To this effect, traditional chemical procedures are gradually being replaced by biotransformations. The β‐lactam antibiotics industry has led the way in the introduction of biocatalysis in the fine chemicals industry by replacing the chemical multi‐step process for the penicillin nucleus 6‐aminopenicillanic acid (6‐APA) by an enzymatic one in the early 1990's. Recently, bioprocesses have been developed for the synthesis of the cephalosporin nucleus, 7‐aminodeacetoxycephalosporanic acid (7‐ADCA) from a penicillin precursor and will shortly be commercialized. Thirty years of research have now resulted in viable enzymatic procedures for coupling the β‐lactam nuclei with D‐phenylglycine side‐chains. The necessary adaptations in the synthesis of the side‐chain donors have likewise resulted in more efficient procedures. 1 Introduction 2 Semi‐Synthetic β‐Lactam Antibiotics: Industrial Production Prior to 1985 3 Biocatalytic Synthesis of β‐Lactam Nuclei 3.1 6‐Aminopenicillanic Acid 3.2 7‐Aminodeacetoxycephalosporanic Acid 4 Biocatalytic Routes to Side‐Chains 4.1 Synthesis of the Side‐Chain Building Blocks 4.2 Synthesis of Activated Side‐Chain Donors 5 Enzymatic Coupling of the Side‐Chains to the β‐Lactam Nuclei 5.1 Chemical Procedures 5.2 Enzymatic Coupling 5.3 Practical Procedures for Enzymatic Coupling6 Conclusion and Future Outlook

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