Introduction: Fragment screening is a successful approach to accelerate drug discovery. Since it handles fragments with weak affinity, sensitive analytical tools are strongly demanded. Areas covered: After a short description of the available techniques employed in fragment screening, this review focuses on Weak Affinity Chromatography (WAC). Details include the origins of affinity chromatography and its evolution to WAC and the basic principles for affinity measurements. Preparation of columns for the immobilization of soluble target proteins and the development of lipodiscs for the incorporation of membrane proteins are described. The authors also discuss the advantages and limitations of WAC and compare it with other established techniques. Expert opinion: Although WAC is a suitable technique for fragment screening, with increased throughput, in particular, if coupled to mass spectrometry, it has not yet found the widespread application it deserves. A limiting factor may be the necessity for in house column preparation. In the future, the potential commercialization of columns with some important soluble protein targets would facilitate the application of WAC. The immobilization of membrane proteins on lipodisks is an area for further investigation, as is the comparison of WAC with other established methods since relevant information is still at a low level.