The festival was the brainchild of Columbia University physicist Brian Greene and his wife, Emmy Award-winning television journalist Tracy Day.

According to Greene, their idea fell on open ears wherever they went, and the most frequent reaction to their proposal was the expression of disbelief that a festival like this did not already exist in New York City.

Preceding the public events was the invitation-only World Science Summit on May 28, 2008; New York City Mayor Michael Bloomberg opened the Festival.

Participants included Nina Fedoroff (Science and Technology Advisor to U. S. Secretary of State, Condoleezza Rice), biologist David Baltimore and cancer researcher Harold Varmus.

Louis E. Brus and Sumio Iijima shared the nanoscience prize for their contributions to the science of quantum dots and carbon nanotubes, respectively.

Pasko Rakic, Thomas Jessell and Sten Grillner were awarded the neuroscience prize for their research into how neuronal networks develop and communicate.

A number of events explored the interface between science and the arts; for instance, a panel including psychologist Nancy C. Andreasen, choreographer and dancer Bill T. Jones, and actor and writer Michael York focused on the scientific study of creativity.

Other audiences saw physicists Lawrence Krauss and radio host Ira Flatow presenting modern cosmology, paleontologist Richard Leakey exploring the sixth extinction, soundscape ecologist Bernie Krause reflecting on the loss of biophony, and chemist F. Sherwood Rowland and Rensselaer Polytechnic president Shirley Ann Jackson discussing new ways of satisfying humanity's energy needs.

Alan Alda revisited his role as Richard Feynman in Peter Parnell's play QED in a staged reading at Columbia University's Miller Theatre, and the choir of the Abyssinian Baptist Church joined Oliver Sacks in an exploration of music and science.

For the festival's first event, New York City high-school students interviewed robotics expert Cynthia Breazeal and physicist Leon Lederman on-stage, moderated by MTV's SuChin Pak.

Another event was presented by the Disney Imagineers, who explored the science of special effects and amusement park technology, from roller coasters and fireworks to motion capture and artificial fog.

Both Good Morning America and Science News focused on the potential of the festival to inspire the next generation of scientists and "make geek chic".