Using the "one-bead one-compound" (OBOC) combinatorial library method to directly screen intact cancer cells and normal cells, we were able to discover ligands that bind specifically to the cancer cell surface. Highly focused encoded OBOC combinatorial peptide or peptidomimetic libraries were then used to further optimized these lead compounds into high-affinity and high-specificity cancer targeting agents. When conjugated to appropriate reporters, these ligands can be used as effective imaging and therapeutic agents for cancers. The cyclic peptide that targets alpha3 beta1 integrin of ovarian cancer was labeled with 64-Cu and the PET study showed that the peptide was able to localize a small tumor nodule in a nude mouse. The high-affinity peptidomimetic ligand that targets activated alpha4 beta1 of lymphoid malignancies, when conjugated to near infra-red dye or [111-In]DOTA was able to detect lymphoma xenograft with high specificity. Work is currently undergoing in our laboratory to develop these ligands into effective therapeutic agents against cancers. These include the use of the high affinity ligands to deliver 90-Y or liposomal and nanoparticle drug to the cancer.