Horatio investigates the murder of a model intentionally run down outside of a Miami hotel by a driver who fled the scene. When the evidence leads to a suspect, governmental red tape puts an unexpected twist on the proceedings. Horatio and Yelina begin to confront their feelings for one another.

Horatio is driven to find his brother's killer and protect the niece he never knew existed when a woman shows up with Ray's illegitimate child. The team explores a voyeuristic Internet site in connection with a stockbroker's murder.

When a teenage girl returns home from a big party night at an underage nightclub to find her parents murdered, the search for the killer leads Horatio to New York City. Before he arrives, the New York detectives, led by Detective Mac Taylor, are called out to investigate the shooting of an undercover police officer – who, it turns out, is the lead suspect in the Miami case. However, the medical examiner determines that he has been dead for 72 hours and could not even have been alive at the time of the double-murder in Miami. After further investigation, Horatio and Mac determine that the real killer murdered the New York cop, then used his ID to get to Miami, and is still on the loose.

After a large yacht slams into a major Miami bridge, the team finds that the man steering the boat was shot and killed before the accident. The victim's wife reveals that their son had been kidnapped and her husband was handing over the ransom – three million dollars worth of jewels. But when the team learns that the jewels were fake, the investigation leads them into a dangerous situation at a jewelry shop that may contain crucial evidence, where Horatio must face the unimaginable when one of the team is killed in the line of duty.

When the CSIs find a woman swallowed whole and killed by a gigantic snake, they uncover a covert drug smuggling operation. Evidence leads Horatio and the team to a drug smuggling operation where large snakes are suspected of be being used to bring illegal drugs into the country to avoid detection by customs. However, when Horatio finds that Clavo Cruz, a nemesis of Horatio's who hides behind his diplomatic immunity, may be behind the operation, the team must find a legal way to put the criminal behind bars. Meanwhile, Wolfe must find the truth when two women each claim that they are the real victim of identity theft and the other is the culprit.

An axe murderer on death row is given a stay of execution just moments before it was to take place, on the grounds that there may have been tainted DNA analysis used at his trial. Now, without using any DNA evidence, the team must race against time and reexamine all of the physical evidence in the case, just as they get a call on a new double murder that looks suspiciously like the case they're working on.

While investigating the murder of man hired to make dirty bombs that terrorists intend to set off in Miami, Horatio finds the bloody fingerprint of his brother, Raymond, who he believed to be dead. However, when Raymond's son is kidnapped, he emerges from deep undercover and the estranged brothers must work together to save the boy. Meanwhile, while processing a crime scene, an unknown assailant holds a gun to Calleigh's head and, after a deadly confrontation in her gun lab, she is left doubting that she can continue as a CSI.

The team must find the connection between the two crime scenes; the killing of a drug dealer and the rape of a well-off family member.

(Crossover episode with CSI: New York, Season 2 Episode 7.)

A crossover episode that concludes on "CSI NY" begins with a convicted serial killer who escapes after sabotaging an airplane that was flying him from New York to Miami, where he allegedly buried a body. After fleeing the crash site, the man goes on a killing spree and abducts a college student. Mac Tayor arrives to help Horatio track the killer since Mac originally arrested the man in New York.

The Mala Noche gang trial is obstructed when the defendant goes free with the help of the witness who is testifying. When a hit ordered by the Mala Noche gang on Horatio finds the people he loves lives are in danger. Delko finds that an ex-lover is disturbing any woman who he is now close to.

The dead body of a celebrity is found at an A-list party. They soon discover that the murder is linked to a “death pool,” where gambling occurs on an offshore ship. A counterfeit ring is also discovered where 100-dollar bills are produced in this 100th episode of CSI: Miami.

There's a serial killer on the loose marking all of his victims with a Y on their chests and one or more of the csi's lives are in danger in this season 5 finale