Incorporation of fluorine into an organic compound can favourably alter its physicochemical properties with respect to biological activity, stability and lipophilicity. Accordingly, this element is found in many pharmaceutical and industrial chemicals. Organofluorine compounds are accepted as substrates by many enzymes, and the interactions of microorganisms with these compounds are of relevance to the environment and the fine chemicals industry. On the one hand, the microbial transformation of organofluorines can lead to the generation of toxic compounds that are of environmental concern, yet similar biotransformations can yield difficult-to-synthesise products and intermediates, in particular derivatives of biologically active secondary metabolites. In this paper, we review the historical and recent developments of organofluorine biotransformation in microorganisms and highlight the possibility of using microbes as models of fluorinated drug metabolism in mammals.