Nucleoside analogs are first line chemotherapy in various severe diseases: AIDS (acquired immunodeficiency disease syndrome), cytomegalovirus infections, cancer etc. However, most of these compounds suffer from poor bioavailability via oral route. In order to get around this drawback, researchers have imagined many strategies including drug metabolism inhibitors, bio adhesive nanoparticles, amino ester prodrugs, as well as enhancing absorption by increasing drug lipophilicity. This paper illustrated these approaches by developing their application to some nucleoside analogs. Moreover, some of these strategies were very successful and some resulting compounds are now approved by FDA (Food and Drug Administration).