One major challenge in nanomedicine is the selective delivery of nanoparticles to diseased tissues. Nanoparticle delivery systems require targeting for specific delivery to pathogenic sites when enhanced permeability and retention (EPR) is not suitable or inefficient. Nanoparticle functionalization is a widely-used technique for targeting ligand conjugation; these ligands possess inherent abilities to direct nanoparticle selective binding. This review illustrates methods of ligand-nanoparticle functionalization, provides a cross-section of various ligand classes, including small molecules, peptides, antibodies, engineered proteins, or nucleic acid aptamers, and discusses some unconventional approaches currently under investigation.