The film and video work of James Fotopoulos has been shown internationally at many festivals and sites including the International Film Festival Rotterdam, the New York Underground Film Festival, the Sundance Film Festival, the Walker Art Center, Momenta Art and the Andy Warhol Museum, among others.

In 1998 Fotopoulos founded Fantasma, Inc. for the production of his second feature film Migrating Forms (1999). In 2002 he had a retrospective at Anthology Film Archives and was exhibited in the 2004 Whitney Biennial. In 2005 he received a Creative Capital Grant for his in-progress interdisciplinary epic on the life of Richard Nixon, published the first of many books of drawings The Lime Book, and completed an installation for the 2005 Contour Biennial for Video Art. In 2006 with Grove Press founder Barney Rosset he created an experimental video biography on Rosset and an adaptation of an unpublished screenplay by Eugène , of which the latter premiered at the New York Museum of Modern Art. .

In 2008 he directed two videos based on screenplays by artist Raymond Pettibon, the first of which is premiering in 2012 along with recent videos Chimera, Thick Comb and Alice in Wonderland at Anthology in tandem with his first solo exhibition of drawings at the Microscope Gallery. Currently in production are the feature films Dignity and collaboration with artist Laura Parnes Ten Ways of Doing Time.