Ever since the invention of SELEX (systematic evolution of ligands by exponential enrichment), there has been rapid development for aptamers over the last two decades, making them a promising approach in therapeutic applications as either drug candidates or diagnostic tools. For therapeutic purposes, a durable performance of aptamers in biofluids is required, which is, however, hampered by the lack of stability of most aptamers. Not only are the nucleic acid aptamers susceptible to nucleases, the peptide aptamers are also subjective to degradation by proteases. With the advancement of chemical biology, numerous attempts have been made to overcome this obstacle, many resulting in significant improvements in stability. In this review, chemical modifications to increase the stability of three main types of aptamers, DNA, RNA and peptide are comprehensively summarized. For nucleic acid aptamers, development of modified SELEX coupled with mutated polymerase is discussed, which is adaptive to a number of modifications in aptamers and in a large extent facilitates the research of aptamer-modifications. For peptide aptamers, approaches in molecular biology with introduction of stabilizing protein as well as the switch of scaffold protein are included, which may represent a future direction of chemical conjugations to aptamers.