The original ran for 15 seasons and spawned three other series: CSI: Miami, CSI: NY and CSI: Cyber along with a generation of similar shows, such as Bones and the hyper-popular NCIS series. Over its 16 years, the franchise featured stars ranging from David Caruso to Ted Danson to Patricia Arquette to Gary Sinise.
In one week in 2006, a Nielsen rating found that 70 million people watched one of the CSI shows.
The premiere almost never aired, and when it finally did, it was considered a black sheep, just a fun experiment while CBS focused on its real show, according to TV historian and critic Alan Sepinwall.
Even then, critics certainly weren't blown away. Sepinwall himself admits it was the show about which he was "most wrong in predicting its commercial success based on the pilot".
"If you asked most CBS executives at the time, they would say that they were very high on The Fugitive and weren't quite sure how their viewers would react to CSI, but that it seemed like an interesting experiment," Sepinwall wrote.
"Disney lost a fortune on CSI not once, but twice: First when the network didn't order it to series, then when their in-house studio decided to give up their ownership stake in the show, rather than throw what they felt was good money after bad."
He, and many others, guessed wrong partly because the show was different from most other easily digestible fare that aired during prime time, particularly the crime shows it was often lumped in with.
While other crime shows focused on the more confrontational aspects of law enforcement - the arrests, the foot and car chases, the interrogation room - CSI dramatised the gathering of forensic evidence, the DNA testing, the science that would take place behind the scenes in those other shows (if it existed at all).
That was 16 years ago, of course. That was before CSI became the most watched TV show not in America but on Earth and not for just one year but for five.
The show became so popular, it had real-world effects.
According to The Anthropology Graduate's Guide, it, along with its imitators, "stimulated a new generation of students to enter the field of forensic anthropology".
In partnership with CBS , the Fort Worth Museum of Science and History was granted US$2.4 million ($3.5 million) from the National Science Foundation to create a forensic science exhibit, which opened in 2007 at the Museum of Science and Industry in Chicago, before touring the nation.
That's not to say it didn't also cause controversy. Its stories often - if not mostly - centred on violent crimes, many of them sexual in nature. The Parents Television Council called it TV's least family-friendly show in 2003, citing plotlines involving cannibalism, S&M sex clubs and snuff films.
US prosecutors even began complaining that the show had real-world effects in the courtroom. They claimed juries now expected an unrealistic amount of forensic evidence.
In the show, prosecutors are often armed with perfect blood matches and nearly indisputable DNA evidence nailing a perp to the scene of a crime. Real life isn't that simple.
This was such a prevalent complaint that it became termed the "CSI effect", NPR reported. The National Institute of Justice even investigated the effect.
"I think that CSI has done some great things for medico-legal death investigations. It has brought what we do from the shadows - where people really didn't want to know and didn't care what we do - to the bright light of day," Mike Murphy, the coroner for Clark County, Nevada, whose office was the model for the original CSI, told NPR in 2011.
"It's also caused some problems. And some of those problems are [that] people expect us to have DNA back in 20 minutes or that we're supposed to solve a crime in 60 minutes with three commercials. It doesn't happen that way," Murphy told NPR.
But those days have passed. In the past few years, the show had suffered declining popularity and, according to Metacritic, declining quality.
That downshift in quality is evidenced by the mixed reactions found on Twitter.
Regardless of how fans felt about the show at its end, one thing's certain: It helped define an era of television, and the imitators it spawned will likely live on for many more years.
Of course, there's always a chance CBS will bring back one of the cancelled spin-offs or create an entirely new one.
Until then, the CBS announcement truly marks the end of an era in television.
CSI forever
16 years of shows
800 episodes
3 other series, including CSI: Miami, CSI: NY and CSI: Cyber