Trained as an engineer, Bob Jesse was at one time a vice president for Oracle, the world's second largest independent software company. In 1993, Jesse founded the Council on Spiritual Practices, a non-profit organization whose mission is "to identify and develop approaches to primary religious experience that can be used safely and effectively, and to help individuals and spiritual communities bring the insights, grace, and joy that arise from direct perception of the divine into their daily lives." From its inception, CSP has acknowledged that psychoactive substances can be useful in the pursuit of such experiences. In 1995, CSP first published their Code of Ethics for Spiritual Guides online.

Jesse is also co-founder of the Rhythm Society (formerly the St. John's Divine Rhythm Society ), an organization dedicated to creating space for direct, experiential forms of spiritual practice by celebrating spirit through music, dance, meditation, and play. For a time, the Rhythm Society produced all-night dance events at an Episcopal church in San Francisco; ultimately, its relationship with the Episcopal church was ended due to controversy. The Rhythm Society continues to sponsor community dance gatherings elsewhere.

Along with Roland Griffiths, Bill Richards, and Una McCann, Jesse was instrumental in the design and completion of a study at Johns Hopkins University that looked into the psychospiritual effects and benefits produced in naive users of psilocybin. This study, and its follow-up surveys, provided evidence that was even more detailed and solid than the original research that inspired it, Walter Pahnke's Good Friday Experiment. Work by Jesse in this area is important because it is not looking to treat disease with psychedelics, as is the focus of most other government-approved research. Rather, it shows that healthy people can receive spiritual and psychological benefits from the careful use of psychedelics.