Abstract The discovery of artemisinin from Chinese medicinal plant, Artemisia annua in 1971, opened a new era in the malarial chemotherapy. This discovery was the beginning of exploring peroxides as potential replacements for the traditional antimalarial drugs such as chloroquine and mefloquine. The structurally simple class of peroxides that emerged from these studies was the 1,2,4,5‐tetraoxanes. This study describes the current status of tetraoxane‐based antimalarials that show significant promises because of their artemisinin‐like activity. Literature from 1999 has been critically reviewed and an attempt has been made to discuss various synthetic methods and structure–activity relationship study among the series of tetraoxane‐based compounds. © 2010 Wiley Periodicals, Inc. Med Res Rev, 32, No. 3, 581–610, 2012