The longest version of the circuit went south through Caltavuturo (whereas the shortest version of the open-road circuit went east just before entry into Caltavuturo, through a mountainous section directly to Collesano) through an extended route through elevation changes, and climbed uphill through the nearby towns of Castellana, Sottana, Madonnuzza and Miranti, twisting around mountains up to the highest point- 1,100 metres (3,600 ft) at Geraci Siculo, dropping down 620 metres (2,030 ft) into Castelbuono, twisting around more mountains and passing through Isnello and the village of Mongerrati and then rejoined the most recent version of the track at Collesano.

Originally a narrow 2-lane country road, the Buonfornello straight became a lot wider in the late 1960's thanks to the development of the Autostrade motorways all over Italy.

To even finish this punishing race required a very reliable car- and it being a slow, twisty circuit it was very hard on the gearbox, brakes and the suspension of a car.

Some manufacturers and entrants, particularly non-Italian ones would sometimes outright skip the Targa because of the difficulty of learning the layout and were unsure if their cars could stand the brutal pace there.

Helmut Marko set the lap record in 1972 in an Alfa Romeo 33TT3 at 33 min 41 s at an average of 128.253 km/h (79.693 mph) during an epic charge where he made up 2 minutes on Arturo Merzario and his Ferrari 312PB.

The lap record for the 148.82 km (92.47 mi) "Grande" circuit was 2 hours 3 min 54.8 seconds set by Achille Varzi in a Bugatti Type 51 at the 1931 race at an average speed of 70.7 km/h (43.931 mph).

[10] The lap record for the 108.00 km (67.11 mi) "Medio" circuit was 1 hour 21 min 21.6 seconds set by Varzi in an Alfa Romeo P2 at an average speed of 79.642 km/h (49.487 mph) at the 1930 race.

Due to safety concerns, especially by Helmut Marko, who called the race "totally insane", the last Targa Florio as a World Sportscar Championship race was run in 1973; when it had become impossible to retain its international status after a number of accidents, two of which were fatal; one which privateer Charles Blyth crashed his Lancia Fulvia HF into a trailer at the end of the Buonfornello straight and was killed; and another where an Italian driver crashed his Alpine-Renault into a group of spectators, killing one.

The Targa's international demise was compounded because of widespread concern about the organizers' ability to properly maintain the race on such a massive circuit, and there were not enough marshals - most spectators sat too close to the roads; and also the international automotive governing body, the FIA, mandated safety walls on all circuits that were going to hold FIA-mandated events from 1974 onwards, and the 44-mile (71 km) length of combined public roads made this simply impossible and totally impracticable, especially from a financial standpoint: the sport's growing professionalism was something the Targa's organizers simply could not keep up with.