Harry Riccobene started dealing in drugs in the 1920s and was first arrested for narcotics in 1932, receiving two years in prison. While the more senior mafiosi generally stayed away from drugs, the younger guys started getting involved during Prohibition. Frank Piccolo got involved in narcotics by the early-1920s and Peter Casella was another figure with early drug convictions in the 1930s. The Lanzetti gang was a significant player in the drug trafficking scene at that time, obtaining narcotics from New York and selling them in Philadelphia, but the LCN family avoided getting involved in an organised way. Salvatore Avena (son of boss John Avena) said that his father was warned by Dominick Pollina to stay away from narcotics and the Lanzettis. The general attitude towards drugs was laissez-faire, however. Not wanting to get involved but not willing to turn down the proceeds.

Associates Raymond Martorano and Frank Sindone had drug convictions by the 1950s. Riccobene was sent away for a long stretch in 1952 and Casella got stung by undercover agents in 1958 bringing 37 pounds of heroin down from New York (it was also believed that Pollina and Angelo Bruno were financing his deals). Joseph Ida was linked in his FBI files to narcotics being smuggled from France and Italy. Marco Reginelli, Felix DiTullio and Louis Campbell were identified as regular opium users. After the heat that came down on drug traffickers in the 1950s however (and the lengthy sentences received by Riccobene and Casella) Bruno got more cautious and was picked up on tape a few times warning his guys not to associate with known dealers or else risk being caught up in drug cases.

The Sicilian Gambinos set up shop in South Jersey in the early 1970s with Bruno's blessing. Some members of the Philadelphia family would buy heroin from the Gambinos and sell it to non-mob distributors, who would then sell it on to street dealers. Bruno was not opposed to this but was opposed to the family getting into drugs in an organised fashion. This irritated members involved in heroin who knew they could make several times more from junk if they were allowed to do so in a coordinated fashion. Antonio Caponigro was one of these guys who wanted to get more involved in drugs.

Raymond Martorano got involved in meth in a big way and Bruno made money off of that. Harry Riccobene got involved in meth himself and, when Scarfo took over, he was organising the shake downs of drug dealers and P2P importers. Ralph Natale was also involved in meth once he became boss.