Radiotherapeutic drugs and medical imaging agents, although used for different purposes, both benefit from precise targeting. When systemically administered, either would be most useful if designed to find and bind only a tumor, single type of cell, or unique molecular assembly thereon. In this Account, we examine the use of small peptides, natural and synthetic, to create biochemically specific molecular imaging agents and radiotherapeutic pharmaceuticals, discussing three distinct examples. In one project, a small natural peptide known to target members of the bombesin family of receptors was chemically attached to a strong, versatile metal chelator, DO3A, through a series of small-molecule linkers. The linkers powerfully affected not only binding strength for the bombesin receptors, tissue distribution, and tumor uptake in vivo but also receptor subtype specificity. When the assembly is combined with an active metal ion for human trials, the versatility of the DO3A (dodecanetriacetate) chelate affords choices in selecting the metal ion for different purposes: lutetium for a combination radiotherapeutic and diagnostic agent, (177)Lu-AMBA, and gallium for a positron emission tomography (PET) imaging agent, (68)Ga-AMBA. We also created small (approximately 5-kDa) bivalent peptides, each composed of different chemically linked peptides derived from phage display. The monomer peptides bound to the same target protein, VEGF-R2, a primary target of vascular endothelial growth factor (VEGF), the angiogenesis-stimulating protein. Several families of the monomer peptides did not compete with one another for the binding site on VEGF-R2. Their combination into fully synthetic hetero-bivalent molecules yielded subnanomolar K(d) values and greater than 100-fold improvements over homo-bivalent molecules. Biological activity was evident in the hetero-bivalents, whereas none or very little existed in homo-bivalents, monomers, and monomer mixtures. In ultrasound imaging, tiny bubbles (2 microm in diameter) filled with inert gas can be used as effective contrast agents. By coating the shell of such bubbles with the peptide TKPPR (a tuftsin antagonist), we created contrast agents that bound unexpectedly to cultured endothelial cells expressing angiogenesis targets; the binding was attributable to a previously unnoticed and powerful multivalency effect. TKPPR binds specifically to neuropilin-1 (NP-1), a VEGF co-receptor, but only when multimerized is it avid. Tuftsin, a small peptide derived from immunoglobulin G (IgG) that binds to macrophages during inflammation, has been studied for over 30 years; the receptor has never been cloned. Our results led to new conclusions about tuftsin, NP-1, and the purpose, heretofore unknown, of exon 8 in VEGF, which appears to be involved in NP-1 binding. Our disparate projects demonstrate that small-peptide targeted molecules can be very versatile in drug discovery in combination with classical medicinal chemistry. In particular, multivalent interactions can lead to unpredictable and useful biochemical information, as well as new drug candidates.