Santiago's career took off in 1984 in Puerto Rico and the rest of Latin America as a soloist, forming his own band, and recording songs including: "Tú me quemas" (You Burn Me), "Qué Locura Enamorarme de Ti" (What Madness To Fall in Love With You), "Me Fallaste" (You Failed Me), Antidoto y Veneno (Antidote and Venom), "Tu Me Haces Falta" (I Need You), his best known hit "Lluvia" (Rain, not to be confused with Menudo's hit of the same name), and many others. His fame eventually spread to Europe and the United States, making him one of the most popular Salsa singers in the late 1980s and early 1990s. He was one of the main singers of "Salsa romántica" ("romantic salsa").
His first major recording on an international label was with Sony Music in 1999. He also recorded for the TH, EMI Latin, and Polygram labels, including the well regarded production inspired by the music of Rafael Hernández, entitled "Enamorado". In 1999 he released Celebration: Epic Duets. He was joined on that album by other stars in the Latin music scene, Víctor Manuelle, Huey Dunbar and Elvis Crespo. The album was named one of the best recordings of 1999 by the National Foundation for Popular Culture.