On September 25, 1997 Mashal was the target of an assassination attempt carried out by the Israeli Mossad under the direction of Prime Minister Benjamin Netanyahu and his Security Cabinet. Ten Mossad agents carrying Canadian passports entered Jordan, where Mashal was living, and injected him with a toxic substance. At the time of the assassination attempt Mashal was considered Hamas' Jordanian branch chief.
Jordanian authorities discovered the assassination attempt and arrested two Mossad agents who had engaged in the attempt. Jordan's King Abdullah then demanded that Benjamin Netanyahu turn over the poison antitode, and at first Netanyahu refused. As the incident began to grow in political significance, however, American President Bill Clinton intervened and forced Netanyahu to turn over the antidote. The incident would lead Clinton to say of Netanyahu that he "cannot deal with this man. He is impossible." 
Jordanian authorities later released the Mossad agents in exchange for the release of Sheikh Ahmed Yassin, the founder and "spiritual leader" of Hamas who was serving a life sentence in an Israeli prison.
In August of 1999, probably in reaction to pressure from the Clinton Administration, Jordanian police issued an arrest warrant for Mashal in advance of a visit to the country by then-Secretary of State Madeleine Albright .
In October of 2002 Mashal is believed to have met with Saudi Crown Prince Abdullah to discuss the Israeli-Palestinian conflict during the World Assembly of Muslim Youth in Riyadh. The outcome of that meeting is unknown, although supposed Hamas documents discovered by Israeli security forces described the meeting as "excellent" .
Recently, Mashal has acted as a vocal critic of Palestinian Authority Chairman Yasser Arafat, often refusing to follow directives issued by the PA regarding cease fires with Israel. Mashal is considered a key force behind this policy, along with Sheikh Ahmed Yassin.