The TSPO (translocator protein), also known as the peripheral benzodiazepine receptor, is upregulated in the brain of subjects suffering from neurodegenerative disorders such as Alzheimer's, Parkinson's and Huntington's disease. Moreover, this overexpression has been proved to be linked to microglia activation making thus the TSPO a marker of choice of neuroinflammatory processes and therefore a potential target for the development of radioligands for positron emission tomography imaging. The discovery of selective TSPO ligands and their labelling with the short‐lived positron‐emitter isotopes carbon‐11 and fluorine‐18 emerged in the mid‐1980s with the preparation of the 3‐isoquinolinecarboxamide [ 11 C]PK11195. To date, an impressive number of promising compounds—[ 11 C]PK11195‐challengers—have been developed; some radioligands—for example, [ 11 C]PBR28, [ 11 C]DPA‐713, [ 18 F]FEDAA1106 and [ 18 F]DPA‐714—are currently used in clinical trials. As illustrated in this review, the methodologies applied for the preparation of these compounds remain mainly [ 11 C]methylations using [ 11 C]MeI or [ 11 C]MeOTf and S N 2‐type nucleophilic aliphatic [ 18 F]fluorinations—two processes illustrating the state‐of‐the‐art arsenal of reactions that involves these two short‐lived radioisotopes—but alternative processes, such as [ 11 C]carbonylations using [ 11 C]CO and [ 11 C]COCl 2 as well as S N Ar‐type nucleophilic [ 18 F]fluorinations, have also been reported and as such, reviewed herein.