With dynamic combinatorial chemistry (DCC) compound libraries can be generated from reversibly reacting building blocks. Within these libraries, all constituents are continuously interconverting, ultimately reaching a thermodynamic equilibrium. The most intriguing feature of dynamic libraries is their adaptability, i.e. they can respond to an external stimulus with a shift in their equilibrium composition. For instance, a target protein can bind high-affinity library members, stabilize them, and induce their amplification. This approach is called target-directed DCC (tdDCC). The ability to self-screen make tdDCC a valuable tool for drug discovery. Section I of this thesis contains several introductory chapters. In Chapter 1, a short historic background of drug discovery and target-assisted approaches is given, followed by a review on tdDCC and its application in biological and pharmaceutical research (Chapter 2). Furthermore, the field of glycobiology and carbohydrate-based drug discovery is shortly introduced in Chapter 3. In Section II, work on the bacterial adhesin FimH is presented. FimH is a mannose-recognizing lectin expressed by uropathogenic E. coli, which are the main cause of urinary tract infections (UTI). The adhesin plays a crucial role in the development of UTI, mediating the initial contact between bacteria and bladder epithelium. Antagonizing FimH is a promising treatment strategy and poses an alternative to classical antibiotics. In Chapter 4, background information on UTI, FimH, and antagonist development is given. In Chapter 5, in-depth work on tdDCC with FimH is presented. Starting from aldehyde and hydrazide building block, we used reversible acylhydrazone formation to generate dynamic libraries in presence and absence of FimH. During the method development, careful evaluation of the sample preparation, the analysis, and the data procession turned out to be essential. Only with the optimized protocol, the changes in the library composition inflicted by the target protein aligned with the affinities of the library members for FimH. Chapter 6 describes the adaption of the tdDCC approach for a larger library. Interestingly, a linear relationship between the amplification rate of compounds in the tdDCC experiment and their affinities was found. Furthermore, the potentially hazardous acylhydrazone moiety was replaces by various bioisosteres, while managing to retain the affinity of the parent compound. In addition to the work on tdDCC, the thesis contains two further projects on the FimH target. In Chapter 7, a phosphate-prodrug strategy to improve the oral bioavailability of FimH antagonists is described, whereas in Chapter 8, a novel method to assess kinetic binding characteristics from isothermal titration calorimetry (ITC) measurements, so-called kinITC, is evaluated. In Section III, work on the C type lectin E-selectin is presented. This cell-adhesion protein is expressed by activated endothelial cells and plays a crucial role in the recruitment of leukocytes to the sites of inflammation. After an introduction to the protein and prior antagonist development (Chapter 9), an attempt to establish a tdDCC method, again employing reversible acylhydrazone formation, is described in Chapter 10. During the development, major obstacles were found to be non-specific binding of library constituents to the employed plastic tubes and proteins present in the libraries. Nevertheless, the acylhydrazone library was synthesized and subsequently screened with microscale thermophoresis (Chapter 11). Encouragingly, one library member showed only a two-fold diminished affinity as compared to sialyl Lewisx, the natural ligand of E-selectin, while exhibiting higher ligand efficiency. Finally, Section IV contains a short summary and an outlook on the future of tdDCC. The work presented herein clearly shows the capabilities, but also the constraints of the application of tdDCC to drug discovery.