In 1998, following a mass burning of abductees in Kazakhstan and then another on Skyland Mountain, the Well-Manicured Man expressed, during a meeting of the Syndicate, that he feared the Colonists would intervene in the situation if the Syndicate did not determine who was responsible for the group incinerations. (TXF: "Patient X")
Soon thereafter, the Well-Manicured Man – while alone with Alex Krycek, aboard the Uroff-Koltoff Star of Russia – started to realize that Krycek had a vaccine against the alien "black oil" virus and remarked that such a development would mean that resistance against the Colonists had just become possible.
After another mass burning took place (this time, at Pennsylvania's Ruskin Dam) and the Syndicate discovered that a group of faceless aliens had been responsible for the attacks, the Well-Manicured Man commented that a faceless alien who had recently been captured by the Air Force was a resistance fighter against the Colonists. The Well-Manicured Man also implied that a war had begun between the Colonists and the rebels. (TXF: "The Red and the Black")
Later that year, the Well-Manicured Man privately told FBI Special Agent Fox Mulder that the Syndicate had been working cooperatively with the Colonists while also secretly working to develop a cure against the alien virus. After giving Agent Mulder the vaccine that the Syndicate had obtained from Krycek, the Well-Manicured Man revealed to Mulder that the Colonists did not yet know of the vaccine's existence. (The X-Files Movie)
In 1999, Cassandra Spender told Mulder and his FBI partner, Dana Scully, that her own son, Jeffrey, was in league with the men that had been working with the Colonists over the past fifty years. (TXF: "Two Fathers")
After Marita Covarrubias informed Mulder that she had been a test subject for the development of the alien virus vaccine and that those experiments had been secretly conducted, Mulder added that the tests had been held secret from the Colonists, specifically.
In a subsequent private discussion between Mulder and the Cigarette Smoking Man, the CSM recalled that – prior to the abduction of Mulder's sister, Samantha – the Syndicate had agreed to cooperate with the alien Colonists and ally themselves with the Colonists despite the objections of Mulder's father, Bill. The CSM further explained that the reason Samantha Mulder had been abducted from the Mulder family home was that Bill Mulder had been late to understand the necessity that, in common with the other Syndicate members, he would have to surrender one of his family members to the Colonists.
Once the Syndicate began to make final preparations for colonization, Krycek told Jeffrey Spender that the Syndicate members would be transported by the Colonists and begin medical preparations to receive hybrid genes. (TXF: "One Son")
The colonists later abandoned their plans to invade earth as they found it too unhabitual due to global warming. (TXF: "My Struggle III") A shadow group began feigning alien abductions as a cover for their experiments. (TXF: "My Struggle) Surviving Syndicate member the Cigarette Smoking Man planned to use an alien virus to depopulate the earth. (TXF: "My Struggle II", "My Struggle III")