(North to South)
Much of Muskoka, especially around Georgian Bay or any other body of water, is private property. Towns such as Honey Harbour are filled with fenced cottages whose residents may not be very welcoming. Unless you are renting a cottage, it is better to stay away from the towns and instead turn to the many provincial parks in the area. These offer parking, facilities, access to the water and campgrounds.
If you are interested in boating, do not expect to find boat rentals by Muskoka's lakes. If you drive in through Barrie, it has several rental shops you can stop at before heading further north.
You can reach Muskoka on a day trip from Toronto. Since it is such a large area, travel times can vary. From Toronto, most tend to take Highway 400 north, through Barrie, then have a choice of whether to continue on the 400 or change to Highway 11. The former generally takes you to western areas of Muskoka (i.e. Port Severn, Midland), while the latter takes you to the more well known cities of the area (i.e. Gravenhurst, Bracebridge, Huntsville).
Since there are so many lakes between the two highways and around them, there are hundreds of winding "cottage" roads taking a traveller to more specific areas and smaller towns, such as Bala and Rosseau. The main highways between the major two are highways 169, 118, and 69.
Six Mile Lake Provincial Park [http://www.ontarioparks.com/english/sixm.html]. A park right off the 400. Parking, campgrounds and facilities available. Allows access to Six Mile Lake, perfect to explore on canoe. Much of the coast is private property, but still a great Muskoka experience. Ideal for a day trip.
May, early Spring for the areas, is peak time for blackfly and mosquitoes.