The Targa Florio was not so much a race as it was an ordeal. Established in 1906  a single lap was approximately 92 miles. Besides the course which traversed mountain roads unchanged since the Punic Wars, there were severe changes in climate, bandits and wolves. Each hairpin competed with a sheer abyss for the driver's attention over a 3 lap race of 277 miles. Initially there were few rules and the event was open to standard cars of which at least ten identical models had been built. The first race was held on the sixth of May. Only ten cars made it to the starting line due to a dock strike in Genoa. The race would be one of attrition that included among its victims, Vincenzo. One of the entrants was a husband and wife team, the wife serving as the mechanic. Unfortunately no record of their experiences or whether their marriage survived exists. Two cars suffered from water being mistaken for gasoline and required the complete draining of each car's fuel tanks.   After nine hours the race was over and the winner for the Italia team was Alessandro Cagno at an average speed of 29.06 mph. The race proved very popular with the local populace and next years race brought more than 50 entries. In 1907 the race was held on April 22. Like its younger cousin, the Mille Miglia, this race could only be won by driving flat out and after the inaugural race the returning teams had a better understanding of the conditions in which this race was run. Fiat's entry led by Vincenzo Lancia and Felice Nazzaro would be one of the early favorites. At the end of the first lap it was Lancia in the Fiat in the lead. After a slow start the Darracq of Louis Wagner began to gain on the leaders. Soon he passed the first lap leader, Lancia, only to find himself second behind Nazzaro. Still he came, and soon he could see Nazzaro just ahead of him. But alas his engine revs shot up yet his car slowed down and then he found the reason, a broken drive shaft. Nazzaro won the second Targa Florio and since he was known to many of the locals, his victory was very popular with the fans. The third Targa Florio only had thirteen entries after the French decided to stay away. The race was won by Vincenzo Trucco in a Isotta Fraschini.

The fourth Targa was almost canceled when an earthquake struck along the eastern coast and the town of Messina. The deaths of more than 155,000 of its citizens was the result. Still Vincenzo was able to keep the race going for the next few years but the future looked bleak. In desperation Vincenzo changed the circuit to one lap of approximately 628 miles. Slowly the race was brought back to life only to be stopped during World War 1.

After the war the organizers were determined to restart the race so that in November of 1919 a new Targa Florio would be reborn. The circuit was shortened to 67 miles but the race was increased to four laps for a total of 268 miles. The war had deprived the Targa Florio of the great Peugeot driver Georges Boillot who was shot down in a dogfight with a squadron of German fighters. In his place was his brother André Boillot driving a 2 1/2 liter Peugeot originally built before the war. Another entrant of later note was a twenty-one year old driver, Enzo Ferrari, driving a Lancia in his first major race. The weather for the November race was abysmal and saw Antonio Ascari disappear into the distance, or more accurately into a ravine where he was rescued after the race. The circuit was a muddy mess as were the drivers. But Rene Thomas, driving a Ballot was serenely in the lead, or at least he was until his frantic crew was finally able to warn him of a fast approaching André Boillot. But for Thomas it was not enough as the Peugeot of Boillot flashed past. Only a mistake by Boillot could save Rene Thomas now, but still he could not give up and thus increased his speed. For Boillot all that was left was a mad dash down the finishing straight. Racing to the point of exhaustion he braked for the final corner - but he had braked two late for the treacherous conditions and the back of the car spun and hit the grandstand just thirty feet from the finish line. Dazed and bloodied they Boillot and his mechanic were pushed free from the structure and crossed the line in reverse! Shouts of protest greeted the crew but out from the crowd walked Ernest Ballot, the owner of the rival and second place car convinced a dejected André Boillot to return to his car, drive back to the point of their crash and re-cross the line in the right direction. Sacrificing a possible victory for his own car, Ernest Ballot's decision met with the approval of the crowd and André Boillot was declared the winner where upon he fainted straight away.