Targeted cancer therapies focus on molecular and cellular changes that are specific to cancer and hold the promise of harming fewer normal cells, reducing side effects, and improving the quality of life. One major challenge in cancer nanotechnology is how to selectively deliver nanoparticles to diseased tissues while simultaneously minimizing the accumulation onto the nanoparticle of unwanted materials (e.g., proteins in the blood) during the delivery process. Once therapeutic nanoparticles have been created, very often they are linked or coated to other molecules that assist in targeting the delivery of nanoparticles to different cell types of the body. These linkers or coatings have been termed targeting ligands or “smart molecules” because of their inherent ability to direct selective binding to cell types or states and, therefore, confer “smartness” to nanoparticles. Likewise, “smartness” can be imparted to the nanoparticles to selectively repel unwanted entities in the body. To date, such smart molecules can consist of peptides, antibodies, engineered proteins, nucleic acid aptamers, or small organic molecules. This review describes how such smart molecules are discovered, enhanced, and anchored to nanoparticles, with an emphasis on how to minimize nonspecific interactions of nanoparticles to unintended targets.