The closures will begin at noon on Saturday and continue, in some cases, until 9 p.m. Sunday.
Bay Street, from Queen to Dundas will be closed during that time, along with a number of streets around City Hall.
There will be also be shorter closures on a number of downtown streets, Lake Shore Boulevard, Queen's Quay, Commissioner's Street and Queen Street East, as the marathon progresses through the city.
The full list of closures can be found here.
But organizers says the inconvenience is minor, compared with the event itself.
Thousands of runners will be out on the streets — including some of the best runners in the world — no matter what the weather.
And this year fans along the route will be able to cheer for two very special older athletes.
Faujah Singh, better known as the Turbaned Tornado, tried to become the first 100-year-old to run a marathon, last year.
He completed the 42.2 kilometre waterfront course in Toronto, only to have the record denied because he didn't have the proper documents to prove his age.
This year Singh is back to say thanks to the hundreds of fans who ran alongside him last year.
"God willing I would like to come back again and again," he said through a translator.
But instead of the full marathon, this year he'll be running just five kilometres.
"Although people say I inspire them, they inspire me to keep on going," he said.
Another inspiration will be local hero Ed Whitlock of Milton, Ont., who has set dozens or running records in his lifetime.
Whitlock owns 15 age-class world track and field records and three world marathon records.
On Sunday he hopes to set another - becoming the fastest 81-year-old male to ever run a marathon.
"It's a good course for me," he said Friday. "I've had good times on it and I hope for a good time again this weekend."
To break the record he'll have to run 3:47:04.
"I'm sort of fortunate to be born with good running ability and I try to make the best use of that I can," he said.