Fragment-based drug design is increasingly used to identify suitable scaffolds in drug discovery. Whilst providing many advantages, working with low molecular weight fragments also impose challenges. Apart from inherently weak affinities in combination with low molecular weight, one has to handle solubility issues and secondary interactions that may appear at high concentrations. High sensitivity instrumentation is required to observe and verify binding, and the use of difficult targets increases the need for sensitivity even further. Software tools that take the challenges of working with fragments into account shortens the time to results, and increase the confidence in affinity estimations for LMW fragments. Surface Plasmon Resonance (SPR) is firmly established as a powerful technology within FBDD due to its sensitivity, low target consumption, and high quality information-rich data. In this study we highlight the features of the new Biacore? S200 system. This system is specifically designed for high sensitivity combined with increased productivity in fragment screening and kinetic characterization. With a sensitivity increase of 50% compared to current Biacore systems, it enables screening and characterization at lower surface densities. Using this approach, we will exemplify how working with milli-RU levels of dose response can facilitate routine analysis of challenging targets, and how the work with low surface densities will enable the interpretation of data.