Pesce briefly attended MIT. He dropped out in 1982, working at various software engineering jobs before he joined Shiva Corporation, which pioneered and popularized dial-up networking . Pesce's role in the company was to develop user interfaces. His research in this area would lead him deeper into the questions posed by virtual reality, and in 1991 he founded the Ono-Sendai Corporation, named for a fictitious company in the William Gibson novel Neuromancer. The company's R&D included the development of a key technology for the emerging industry and earned Pesce his first patent for a "Sourceless Orientation Sensor," which is used to track the motion of persons in virtual environments.

This development springboarded Pesce into the development of the Virtual Reality Modeling Language (VRML), with which his name has been synonymous ever since, and into a career which has included extensive writings for both the popular and scientific press, teaching and lecturing at universities and conferences around the globe, performances, presentations, and films.

On 21 October 2003, Pesce relocated to Australia, where he continues to live. He is currently an Honorary Lecturer at the University of Sydney and is a judge on The New Inventors, a nationally televised television program in Australia. He is currently developing a new project called Hyperpeople., and a distributed social networking system called Plexus.

In 1993, Pesce formed the VRML Architecture Group (VAG) for the further development of VRML, the Virtual Reality Modeling Language, which Pesce presented to the world in 1994. The purpose of VRML was to allow for the creation of 3-D environments within the World Wide Web, accessible through a web browser. Working in conjunction with such corporations as Microsoft, Netscape, Silicon Graphics, Sun Microsystems, and Sony, Pesce was able to get the industry to accept the new protocol as a standard for desktop virtual reality.

Pesce began his teaching career in 1996 as a VRML instructor at both the University of California at Santa Cruz and San Francisco State University, where he would later create the school's certificate program in the 3-D Arts. In 1998, Pesce was asked to join the faculty of the University of Southern California, as the founding chair of the Graduate Program in Interactive Media at the USC School of Cinema-Television. From January 2004 through January 2006, Pesce was the senior lecturer in Emerging Media and Interactive Design at the Australian Film Television and Radio School (AFTRS) in Sydney, Australia. He now holds an Honorary Appointment at the University of Sydney. The video available on Google Video "Piracy is Good?" is a lecture by Mark Pesce at the Australian Film Television and Radio School about the future of TV distribution in the age of P2P networks.

• Mark Pesce, The Human Network: Sharing, Knowledge and Power in the 21st Century. projected publication date mid-2009.
• Mark Pesce, Programming DirectShow and Digital Video. Seattle, Washington, Microsoft Press, May 2003.
• Mark Pesce, The Playful World: How Technology Transforms our Imagination. New York, Ballantine Books (Random House), October 2000.
• Aaron Walsh and Mark Pesce, Core Web3D. New York, Prentice-Hall Publishing, June 2000.
• Mark Pesce, Learning VRML: Design for Cyberspace. Cambridge, Massachusetts: Ziff-Davis Publishing, 1997.
• Mark Pesce, VRML: Flying through the Web. Indianapolis, Indiana: New Riders Publishing, 1996.
• Mark Pesce, VRML: Browsing and Building Cyberspace. Indianapolis, Indiana: New Riders Publishing, 1995.

• Introduction to Celia Pearce, The Interactive Book. Indianapolis, Indiana: Macmillan Technical Publishing, 1997.