[2] Simoni was born in Palù di Giovo, in Trentino, and began competing as an amateur with the goal of someday winning the Giro d'Italia.

Prior to his retirement in 2010, Simoni would reveal to the Italian newspaper La Gazzetta dello Sport that the Giro was the one race that attracted him to cycling and which motivated him as a professional.

"[3] Simoni turned professional in 1994 with the Jolly Componibili–Cage 1994 team, but suffered through an inauspicious rookie season, having to cope with the deaths of both his father and older brother.

It was only three years later in 1997 that Simoni won his first professional race, a stage of the Giro del Trentino, while riding for the MG Maglificio–Technogym team of sports director Giancarlo Ferretti.

In a race that saw another mercurial Italian climber thrown off the Giro for doping (Marco Pantani), Simoni was criticized in some sectors of the press for claiming a podium finish without having earned the placing.

Simoni cemented his reputation as a climbing specialist by winning the dramatic Alto de El Angliru stage of that year's Vuelta a España.

After competing with a resurgent Stefano Garzelli, Yaroslav Popovych and Marco Pantani in the high mountains in a hailstorm, Simoni achieved his second Giro d'Italia victory.

[4] Following his successful performance in the Giro, he set his aims on the Tour de France and in several interviews challenged the incumbent Lance Armstrong to a battle in the mountains.

After a strong performance in which he finished second in the Giro di Lombardia (which was won by Cunego in the previous edition), Simoni signed a contract to join Saunier Duval–Prodir.

On the urging of his frame sponsor, Scott USA, Simoni began competing in mountain bike marathon events during the 2006 off-season for road bicycle racing.

Simoni alleged that Basso offered him a stage win in the 2006 Giro d'Italia into Aprica five kilometers from the finish after the two cyclists had broken away from the main field.

Simoni was characteristically frank about his last bid for glory, which poignantly saw him beaten in the sprint for the Cima Coppi KOM prize by the Swiss Johann Tschopp, at the summit of the Passo di Gavia in the penultimate Giro stage.

"[6] The Trentinese explained that his curtain call did not go as planned, though he still claimed to have enjoyed closing-out his storied career by finishing a three-week Grand Tour, one of the most challenging events for an endurance road cyclist: "I've known it was time to retire for awhile [sic] It's been on my mind for the last two years.

"[3] But after finally calling it quits on a professional career that included nearly 600 classified results in UCI-sanctioned events,[7] Simoni was vague concerning his plans for his life after cycling, though he hinted at not being in a rush or under any economic or psychological pressure to immediately engage in a new venture.