The ability of proteins to associate rests at the core of biology. Cellular architecture, information transfer, and chemical specificity rely upon highly precise recognition events; frequently these events involve the assembly of two or more proteins. Given the ubiquitous nature of these relationships, and the knowledge that inappropriate protein-protein binding can lead to disease, it should not be surprising that protein-protein interactions have attracted the attention of scientists in the pharmaceutical industry and elsewhere who are interested in producing inhibitors for use as biochemical tools or therapeutic agents. Indeed, there are ample examples in the literature of the use of antibodies, dominant negative proteins, or medium-sized peptides to inhibit particular protein-protein assemblies. In contrast, the discovery of small "drug-like" molecules that can perform a similar function has proven difficult. A number of special challenges are presented by targeting protein-protein binding in a drug discovery program, some of which may apply generally, and others of which almost certainly do not. In this review, I have attempted to present recent examples of small molecule protein-protein binding inhibitors (PPBIs) that demonstrate the progress that has been made in the last two years toward the goal of specifically inhibiting protein-protein binding for therapeutic advantage using a small molecule. I have avoided discussing peptide inhibitors except in the context of their use as templates for the design of related nonpeptide molecules or where a particular example serves to illustrate important approaches to inhibitor discovery or design. Furthermore, I have endeavored not to duplicate the work of Cochran to whose review the reader is referred for a summary of work published prior to 1999. Finally, I have chosen to omit any discussion of integrin inhibitors; recent reviews of the extensive literature in this area are provided by Holzeman and by Samanen. In organizing this review, I have chosen to divide it into three broad sections, which I have loosely entitled "Inhibitors by Screening", "Inhibitors by Design", and "Future Directions".