Some time prior to 2122, the Weyland-Yutani Corporation detected the signal being broadcast from the derelict on Acheron (LV-426), the middle moon of 3 orbiting the ringed planet Calpamos. While the language was unknown, the company succeeded in deciphering enough of the message to learn it was a warning regarding the deadly species Xenomorph XX121. They subsequently dispatched the USCSS Nostromo to investigate, without the crew's knowledge, leading to initial human contact with the Xenomorph, the death of all but one of the ship's crew and the loss of the Nostromo itself. While the incident and the existence of the Xenomorph was apparently covered up by those involved, in a twist of irony the company later coincidentally established the Hadley's Hope terraforming colony on LV-426.

The company has operated numerous research and development facilities throughout the galaxy, often pursuing top-secret research into illegal or dangerous fields, focussing in particular on the study of the Xenomorph species. Major Weyland-Yutani laboratories included installations on LV-1201 and BG-386, and the Origin Facility on LV-426. These labs often operated under particularly amoral conditions, especially where Xenomorph research was concerned; humans were frequently used as unwilling hosts for the creatures, while some teams were even known to deliberately sacrifice low-level Weyland-Yutani employees as live prey in Xenomorph tests. On BG-386, inhabitants from the planet's civilian colony were apparently abducted for use in research, often under the pretence of being "promoted" to a new position elsewhere on the planet.