"(He is) the master-mind behind the kidnap, torture and murder of DEA Special Agent Enrique Camarena back in 1985," said DEA Special Agent Ramona Sanchez.
The State Department is offering a $5 million reward for information leading to the arrest of Caro-Quintero.
Caro-Quintero served 28 years of a 40-year prison sentence for his crimes when a Mexican court ordered his release last August. Sanchez hopes the billboard and huge monetary reward sends a message to potential drug traffickers or organized crime members.
"They'll have to think twice before planning to execute or kill any law enforcement officer," he said.
The billboard in Phoenix is located on US-60 Grand Avenue, south of 31st Avenue. There are also billboards in San Diego, Los Angeles and El Paso, Tex.
Anyone with information is asked to call 1-866-629-6036 or email CAROQUINTEROTIPS@usdoj.gov