He is perhaps best known today for his 30-year pursuit of the Italian-American gangster Lucky Luciano, but also pursued other criminal personalities in his career; escaped Nazis in South America, deviant Italian Catholic monks, Soviet Communist cocaine smuggling networks, and many others.

[4] In the summer of that year, Siragusa traveled to Turkey to act as a liaison to Turkish police forces, where he helped establish many federal programs there.

[9] In 1951, Siragusa became the FBN Supervisory Agent (equivalent to an SAC) of an office in the United States Embassy in Rome that would be called "District 17," which covered the areas of Europe and the Middle East.

[10][3][11] Out of this office, Siragusa traveled to France, Spain, Portugal, Egypt, Iraq, Iran, and other locations to investigate narcotics.

[3] In 1960, Siragusa was involved in an attempt to rescue CIA personnel imprisoned in Cuba after breaking into the Chinese Communist News Agency there.

[12] Siragusa claimed that the CIA approached him to coordinate domestic assassinations to be performed by his connections in the Italian Mafia, and he rejected them.