Bromodomains are α-helical bundles of approximately 110 residues that recognize acetylated lysine side chains mainly on histone tails. Bromodomains are known to play an important role in cancer and inflammation, and as such, significant efforts are being made to identify small-molecule inhibitors of these epigenetic reader proteins. Here, explicit solvent molecular dynamics (MD) simulations of two bromodomains (BAZ2B and CREBBP) are used to analyze the water molecules that seem to be conserved at the bottom of the acetyl-lysine binding site in most crystal structures of bromodomains. The MD runs suggest that the occupancy of the structured water molecules is influenced by conformational transitions of the loop that connects helices Z and A. Additional simulations in the presence of 50 molecules of cosolvent (i.e., 440 mM of dimethylsulfoxide, methanol, or ethanol) indicate that some of the structured water molecules can be displaced transiently. The residence time in the acetyl-lysine binding site is calculated to be about 1 ns, 2–5 ns, and 10–30 ns for methanol, ethanol, and dimethylsulfoxide, respectively, while the affinity of the three cosolvents for BAZ2B and CREBBP is in the range of 50–500 mM. The results described have implications for ligand design, suggesting that only structured water molecules that do not exchange with cosolvent should be maintained in crystal structures used for docking campaigns, and that hydroxy substituents should be incorporated in the ligand so as to map the structured water molecules replaced by (m)ethanol.