Identifying proteins that interact with small molecules is often a challenging step in understanding cellular signaling pathways or molecular mechanisms of drug action. In this report, we describe the construction of libraries displaying human protein fragments on the surface of yeast cells and demonstrate the utility of these libraries for the study of small molecule/protein interactions. The libraries were used to select protein fragments with affinity for the phosphatidylinositides, PtdIns(4,5)P2 and PtdIns(3,4,5)P3. We recovered cDNA inserts encoding pleckstrin homology (PH) domains, a phosphotyrosine-binding (PTB) domain and a fragment of APOH. The PH and PTB domains are known phosphatidylinositide-binding domains, demonstrating the effectiveness of our approach. Binding of APOH to PtdIns(4,5)P2 and PtdIns(3,4,5)P3 has not been previously reported, and thus represent novel interactions. We expect that this method will be generally applicable to the study of small molecule/protein interactions and may facilitate the study of cellular signaling pathways and mechanisms of drug action or toxicity.