Shoupp was last seen at 3:30 a.m. on Saturday, April 28, 1990, when she left a co-worker's home in Boulder, Colorado. She had spent the evening with her co-workers and was on the way back home when she disappeared. She was supposed to stop at the home of her husband to pick up their two small children. Shoupp never arrived at her husband's home and has never been heard from again. Her dark green two-door 1984 Volvo was later found parked at her residence on Hinsdale off Dry Creek between Holly and University in Littleton, Colorado; neighbors recall seeing the car in its usual space at approximately 7:10 a.m.

Shoupp's friends and family say it is uncharacteristic of her to leave without contacting them, or to miss work without notifying her employer that she would be absent. She worked for a computer conventions planning company in 1990. At the time she vanished she was in the process of a divorce; she had separated from her husband approximately five weeks prior to April 28. There were reportedly domestic violence issues in their relationship.

Shoupp's gym bag disappeared with her; it is red with stripes on each end and contained a change of clothes. Foul play is suspected in Nancy's case, which remains unsolved.