"Justice wasn't done back then," LaFata told Reuters. "We hope that DNA tests and criminal profiling will help us discover the motive behind the crime and establish whether there was more than one assassin."
Fleisher suspects a crime of passion, although he warns that investigative advances and modern technology might lead sleuthers in any number of unexpected directions.
"I think it's solvable," said Fleisher, who has worked as a Philadelphia police officer, an FBI agent in New York, Boston and Detroit, and a U.S. Customs assistant special agent overseeing investigations in Philadelphia.
After 447 years, there won't be piles of evidence for the investigators to examine.
Still, the case was so notorious that many details survived history.
Like many marriageable maidens of her time, Lanza was promised to another in an arranged marriage, according to historian Vincenzo Salerno, of Palermo. At age 14, she wed Don Vincenzo La Grua, the baron of Carini.
Trapped in an unhappy union, Lanza took at least one lover, Vernagallo, who by some accounts was her cousin.
Many historians believe that the couple was killed in November 1563, after La Grua caught his then 34-year-old wife and her lover in bed.
What isn't confirmed was who swung the deadly knife. Some say that La Grua confessed; others say that Lanza's father, Cesare - avenging the dishonor his adulterous daughter brought upon the family - did the deed.
As evidence of Cesare's guilt, Salerno contends that Cesare ordered mounted troops to surround the castle to prevent the lovers from escaping.
Other stories suggest that La Grua was motivated by plans to marry again, or feared that Vernagallo would seek money for fathering children with Lanza.
The viceroy at the time confiscated Cesare's and La Grua's properties as punishment. But adultery was tantamount to a crime in those days, and the bluebloods eventually regained their properties and good names.
Whatever the reality, the case became part of Italian legend, a tale told to scare young Sicilian brides into marital fidelity, Salerno said.
The case will be the oldest that Fleishman has ever investigated. Besides testing his professional skill, Fleishman joked that his priorities during his trip overseas will be "eating good food and practicing my Italian."
Investigators will make a 3-D computer model of the 11th-century castle, and plan to exhume the couple's bodies for possible DNA testing.