It was established in 2005 by the Public Library of Science in association with the International Society for Computational Biology (ISCB) in the same format as the previously established PLOS Biology and PLOS Medicine.

The founding editor-in-chief was Philip Bourne and the current ones are Feilim Mac Gabhann and Jason Papin.

[1] The journal publishes both original research and review articles.

[6] The Ten Simple Rules series then led to the Quick Tips collection, whose articles contain recommendations on computational practices and methods,[7][8] such as dimensionality reduction[9] for example.

In 2012, it launched the Topic Page review format, which dual-publishes peer-reviewed articles both in the journal and on Wikipedia.