The principal focus of the conference is on the development and application of advanced computational methods for biological problems.

The conference has been held every year since 1993 and has grown to become one of the largest and most prestigious meetings in these fields, hosting over 2,000 delegates in 2004.

The main ISMB conference is usually held over three days and consists of presentations, poster sessions and keynote talks.

The origins of the ISMB conference lie in a workshop for artificial intelligence researchers with an interest in molecular biology held in November 1991.

[4] A subsequent workshop on the same topic held in 1992, hosted by the NLM and the National Science Foundation, made it clear that a regular international conference for the field was required.

[5] Having successfully applied for grants from AAAI, NIH and the Department of Energy Office of Health and Environmental Research, the first ISMB conference was held in July 1993, at the NLM.

The conference was chaired by Hunter, David Searls (research associate professor at University of Pennsylvania School of Medicine) and Jude Shavlik (assistant professor of computer science at University of Wisconsin–Madison) and attracted over 200 attendees from 13 countries,[4] submitting 69 scientific papers.

"[3] ISMB 1997 was held in Halkidiki, Greece and marked the foundation of the International Society for Computational Biology (ISCB).

[5] ISCB was formed with a focus on managing all scientific, organizational and financial aspects of the ISMB conference and to provide a forum for scientists to address the emerging role of computers in the biological sciences.

[8] To allow more delegates to attend, it was decided to limit conference locations to North America and Europe.

In January 2007, ISMB and ECCB agreed to hold joint conferences in Europe every other year, beginning with ISMB/ECCB 2007.

This 'return visit' was an experiment intended to reduce the increasing effort required to find suitable conference venues.

[10] The main ISMB conference is usually held over three days and consists of presentations, poster sessions and keynote talks.

[3] Presentations at ISMB 1994 were split further into three themed days, focusing on protein secondary structure prediction, sequence analysis and AI techniques and biochemical applications, respectively.

Notable ISMB keynote speakers have included eight Nobel laureates: Richard J. Roberts (keynote speaker in 1994, 2006), John Sulston (1995), Manfred Eigen (1999), Gerald Edelman (2000), Sydney Brenner (2003), Kurt Wüthrich (2006), Robert Huber (2006) and Michael Levitt (2015).