Following six years of operation CBCS has collaborated with more than 100 academic groups in Sweden, performing small molecule screening campaigns and using medicinal chemistry to optimize compound properties. The first part of the talk will provide a quick overview of these activities with a focus on recent projects, some of which are unpublished. The second part of the talk will focus on microtiter plate applications of the cellular thermal shift assay (CETSA). Recent analysis of the prerequisites for successful progression through clinical phase 2 studies have pointed at a clear need for demonstration of target engagement in the physiologically relevant tissue. CETSA was introduced in 2013 as a novel means to investigate drug induced stabilization of intracellular proteins in the context of living systems. Its rational application in drug and chemical probe discovery processes required the transfer to a high throughput compatible format. Data will be presented for three early applications. Firstly a small molecule screening campaign was conducted in 384-well plates based on a search for stabilizers of human thymidylate synthase (TS) in live cells. The screen identified all drugs directed towards TS within our library and also a novel off-target effect of decitabine, which was shown to inhibit TS after enzymatic activation in the cells. The two other examples are both based on targeting of human p38 (MAPK14), firstly by comparing CETSA responses for a kinase collection with the results in a phenotypic assay measuring TNF-alfa production. In a follow-up study we have carefully examined the details of p38 stabilization as a function of temperature and time, aiming at elucidating better models for quantitative interpretation of CETSA data. This is of essence for understanding of affinity and selectivity of investigated compounds to support dosage calculations.