In recent years pharmaceutical companies have utilized structure-based drug design and combinatorial library design techniques to speed up their drug discovery efforts. Both approaches are routinely used in the lead discovery and lead optimization stages of the drug discovery process. Fragment-based drug design, a new power tool in the drug design toolbox, is also gaining acceptance across the pharmaceutical industry. This review will focus on the interplay between these three design techniques and recent developments in computational methodologies that enhance their integration. Examples of successful synergistic applications of these three techniques will be highlighted. Opinion regarding possible future directions of the field will be given.