In June of 1982 a symposium entitled "Evolution of Genes and Proteins" was held at the State University of New York at Stony Brook in conjunction with the joint meeting of the Society for the Study of Evolution and ther American Society of Naturalists. At that meeting, Dr. Masatoshi Nei encouraged a group of molecular evolutionists to start a new journal called "Molecular Biology and Evolution". With Walter Fitch as Editor-in-Chief and Masatoshi Nei as Managing Editor, the purpose of starting this journal was (1) to engender better communication between molecular biologists and evolutionary biologists, (2) to rapidly publish high quality papers, (3) to make the journal available to an international readership at an affordable price, and (4) to offer a journal that is owned and controlled by the scientific community. To ensure the latter point the Society for Molecular Biology and Evolution was created and held ownership of the Journal. The Society consisted of the Editor-in-Chief, the Managing Editor, and the Associate Editors.

The University of Chicago Press agreed to publish Molecular Biology and Evolution, and Volume 1 of the journal published in 1984, consisted of 6 issues. By 1985 Molecular Biology and Evolution was ranked third among Evolutionary journals on the basis of Impact Factor, exceeded only by Genetics and by Evolution. By 1991 it had become the leading journal in Evolutionary Biology.

In 1992 Masatoshi Nei organized an International Conference on Molecular Evolution at Pennsylvania State University. At that meeting he and Walter Fitch proposed that the Society for Molecular Biology and Evolution become an active society with all individual subscribers to the Journal being members. That proposal was discussed and enthusiastically endorsed by those present at the organizational meeting. Walter Fitch was elected as the first President of the Society, Masatoshi Nei was chosen as President-Elect, Linda Maxson was elected as Secretary-Treasurer, Caro-Beth Stewart was elected as a Councilor and Barry Hall was elected to succeed Walter Fitch as Editor of the Journal effective with production of the 1994 volume, Volume 11. These five individuals were charged with the organization of a functional Society and with the creation of a set of By-laws it was decided that the Society would be officially activated on January 1, 1993.

The Society for Molecular Biology and Evolution is governed by the Council which originally consisted of the President, Past-President, President-Elect, Secretary-Treasurer, and the Editor of Molecular Biology and Evolution. Effective on January 1, 1994 the office of the Treasurer was added to the Council, with Richard Hudson being elected as the Society's first Treasurer. Effective January 1, 1996 the Council was expanded to include three Councilors, each serving overlapping three-year terms.

In 1994, Council decided to assume publication of the Journal itself, thus ending its association with the University of Chicago Press with the completion of the 1995 volume, Volume 12. This decision gave the Society full financial control of the Journal, and Allen Press was chosen to print the Journal for the Society. By the end of 1995 Molecular Biology and Evolution had increased 3.3 fold in size, and it was decided to increase the number of issue from six to ten per volume. Molecular Biology and Evolution has been a monthly journal since 1997 (Volume 14).

Editors of the Journal
• Walter M. Fitch and Masatoshi Nei (1984-1993)
• Barry Hall (1994-1998)
• Simon Easteal (1999-2003)
• William Martin (2004-2007)