Lee served several brief missions in nearby states and enjoyed success as a preacher, organizer, and healer. He returned to Nauvoo in August 1843 and resumed his duties as a guard at the home of Joseph Smith--a duty he regarded as a privilege. He felt that, "save Jesus Christ," no greater man than the Mormon Prophet had ever lived. When spring came, Lee was called on another mission and went to eastern Kentucky, where he was serving in June 1844 when Joseph and Hyrum Smith were murdered. He returned in August to face a new and threatening situation from neighbors who did not want Mormons in Illinois. Brigham Young, the de facto leader of the Mormons, had started preparations for a move to the West where the Mormons could practice their religion in peace.

Lee was a member of the "Council of Fifty," an organization of Mormon leaders. Lee's role proved to be as a clerk and purchasing agent, positions in which his skills proved valuable. When the first party of pioneers left for the Great Basin in 1847, Lee and his family stayed in Iowa, sixteen miles north of Winter Quarters at "Summer Quarters," to farm and raise crops for those left behind and others to follow. On his own journey across the plains the next year, he was appointed a "Captain of Fifty" and secretary of the train by Brigham Young.