Nucleic acid aptamers, or simply aptamers, are oligonucleotides that bind specific ligands that vary from small molecules to proteins. An aptamer for a specific ligand is routinely identified through the process of systematic evolution of ligands by exponential enrichment, although some aptamers are found in nature as ligand-binding sites of special RNA structures called riboswitches. Aptamers have significant value in biotechnology and for the development of aptamer-based therapeutics. This perspective briefly highlights the tight connection between the journal Chemistry & Biology and in vitro selection technologies over the past two decades. We then focus our discussion on the summary of the current state of the art of aptamer technologies and provide our view of the future challenges and opportunities for the field.