Francesco Cafiso started studying jazz at nine years old in Vittoria, Sicily, sitting in alongside visiting musicians including Bob Mintzer, Maria Schneider, George Gruntz, and Gianni Basso. In July 2002, at the Pescara Jazz Festival, a 13-year-old Cafiso played well enough that Wynton Marsalis invited him onto his 2003 European tour, performing in some of the continent's largest theaters. That same year, he shared a bandstand with pianist Franco D'Andrea at Umbria Jazz, a meeting documented on the 2003 Philology release Standing Ovation at Pescara Jazz Festival 2002.

His recording career started even earlier and moved fast. He debuted as a leader with Very Early! (Philology, 2001) at 12, and by 16 had recorded A Tribute to Charlie Parker, using Charlie Parker's original 1950 with-strings arrangements. That same year he recorded New York Lullaby in New York with David Hazeltine, David Williams, and Joe Farnsworth. By 19 he'd released Angelica on CAM Jazz, his eighth album as a leader, recorded in New York with pianist Aaron Parks, bassist Ben Street, and drummer Adam Cruz. Moody'n, a bebop-repertoire record, followed on Verve Records in 2011.

After 2011, Cafiso pulled back from heavy touring and recording for roughly three years. He returned with a new working band that folded Sicilian folk elements into his jazz vocabulary, releasing the three-disc project 3 in March 2015 (La Banda, Contemplation, and 20 Cents per Note), on which he worked as composer, arranger, and performer across all three records. Around the same period he switched his primary horn from a Selmer Mark VI, the model most saxophonists treat as sacred, to a Selmer Reference 54, saying plainly of the newer horn: "The new saxophone is more rigid. It doesn't respond immediately."

Cafiso's connection to large-ensemble writing deepened through a run of collaborations with the London Symphony Orchestra: Irene of Boston – Conversation avec Corto Maltese (EFLAT Records, 2020), a concept record inspired by a century-old sailing ship wrecked on a Sicilian beach in 2014, conducted by Lee Reynolds; and Where It All Returns, released May 8, 2026, his third LSO record and first orchestral project in six years. Seven interconnected tracks, developed during time Cafiso spent in New York, recorded at Angel Studios in London in September 2025 and at Tube Recording Studio in Fara Sabina that November, with his working trio of pianist Mauro Schiavone, bassist Gabriele Evangelista, and drummer Marcus Gilmore built directly into the orchestral writing. Cafiso has described the approach: "The orchestral writing constantly dialogues with improvisation, maintaining a delicate balance between form and freedom. The orchestra is never merely background, but a living body that breathes with the soloist."

Over more than two decades of touring and recording, Cafiso has shared stages and studios with Hank Jones, Dave Brubeck, Cedar Walton, Mulgrew Miller, Jimmy Cobb, Joe Lovano, Christian McBride, Kenny Wheeler, Gonzalo Rubalcaba, Enrico Rava, and Stefano Bollani, including a 2006 sideman date on the Enrico Rava Quartet's Live in Montreal (EmArcy). In July 2009, the Umbria Jazz Foundation named him "Ambassador of Italian Jazz Music in the World." He founded his own label, EFLAT Records, in 2016, and has been Artistic Director of the Vittoria Jazz Festival, in his hometown, since 2008.

Formal education continued alongside the professional career: a 2006 flute diploma from the V. Bellini Institute in Catania, a 2010 Master's in Jazz from the Corelli Conservatory in Messina, and, in 2023, an Artist Diploma in Jazz from The Juilliard School, a formal return to student life at 34 after three decades of professional playing. In December 2022, the Italian Republic knighted him in its Order of Merit; in March 2026 he received an Honorary Degree in Jazz Saxophone.

Cafiso's playing is rooted in the bebop and hard-bop language he absorbed as a child prodigy alongside veteran musicians, evident in records like Moody'n and A Tribute to Charlie Parker. His catalog has grown into two other distinct directions: orchestral/third-stream writing, developed across three London Symphony Orchestra collaborations that treat the orchestra as an improvising partner rather than a backdrop; and Sicilian folk-jazz fusion, first fully developed on 2015's 3, which folds the melodic and rhythmic character of his home region into a modern jazz small-group format.