Arrived to Rome when he was just twenty years old, after having worked as a plasterer, he was able to gain the trust of cardinal F. Peretti, the soon-to-be Sixtus V, and for him built Villa Montalto on the Esquiline, currently destroyed. But his most significant activity falls during Sixtus V pontificate (1585-90); it's his merit to have projected, and largely executed, the vast plan of town -planning arrangement wanted by Sixtus V almost to underline Rome's universal aspect: the ideal centre of the plan was to be the Basilica of S. Maria Maggiore, from which five wide straight streets, that linked the basilicas and the main monuments visited by the pilgrims, irradiate in star-like shape. Also because of the raising of obelisks and fountains that mark the starting lines of the sights, Rome's urbanistic arrangement executed by Fontana is still fundamental for the monumental aspect of the city in the area comprehended between the Esquiline, Viminal and Pincio hills, along the trajectory of S. Giovanni in Laterano, S. Maria Maggiore and Trinità dei Monti (iter 3). This mainly urbanistic activity are linked to the mostly technical works, such as the construction of the Acqua Felice Acqueduct and the raising of the obelisks in the piazzas of St. Peter's (iter 9), S. Maria Maggiore (iter3), S. Giovanni in Laterano (iter4) and Piazza de Popolo (iter 7) . Perhaps less significant, but nonetheless very noble, is his work as an architect: Fontana built the Manger Chapel in S. Maria Maggiore (iter 3), still in sixteenth century fashion in its architectonic lines but enriched by a polychromy, although sober, that preludes to the baroque taste; he built the Palazzi Lateranensi; he worked on the Quirinal's Palace afterwards completed by O. Mascherino and C. Maderno (iter 3); he collaborated with Giacomo della Porta on the construction, on top of Michelangelo's tambour, of St. Peter's cupola (iter 9) . Once Sixtus V died, the new pope, Clemente VIII, had him removed from his position of pontifical architect, Fontana then went to Naples, where he was nominated (1592) royal architect and Master engineer of the kingdom. In Naples he designed via Chiaia and via di S. Lucia, he erected the Medina fountain, built palazzo Carafa della Spina and gave way to the works for the Royal Palace (1600); also because of reasons of static order, this masterpiece successively suffered various transformations, yet up to this day its façade, divided in three floors by projecting cornices, maintains a rigorous and severe classical balance sharpened also by the employment of the three traditional architectural orders. In his activity as an architect, Fontana had often made use of the collaboration of, besides his nephew C. Maderno, his brother Giovanni Fontana (Melide 1540 – Rome 1614), who was a sanitary engineer, and worked in Civitavechia, Frascati, Loreto and in Rome (Fountain of the Acqua Paola, on the Janiculum (iter 5); in collaboration with C. Maderno). One of Domenico's sons Giulio Cesare (born in Rome), in 1627 was at work in Naples building Palazzo degli Studi.