Follow Hwy 261, turn left at Holpelchen which is abt 70km south to Uxmal.
Keep on the main road which will lead you to Xpuhil/Xpujil, it is a 200km drive in the jungle.
Once you arrive Xpuhil, turn right onto Hwy186 and drive another 50km, the entrance of Calakumul Biosphere Rerserve is on your left hand!
The only reliable way to get to Calakmul is by renting a car. Calakmul is easy to get to but you want to be sure to plan in advance. From Cancun you take Route 307 South until you get to Route 186 and then you turn right going West. I would recommend spending the night in Xupjil which the town right before the turnoff for Calakmul. The turn off for Calakmul will be on your left (South side of the road heading West on 186) about 7 Kilometers from Xupjil. My advice is to start looking for the turn off the moment you leave Xupjil as its a easy turnoff to miss. There is a sign that will let you know you are close but by close I mean its almost an immediate turn after you see the sign. The turn off is marked by dirt road with a wooden gate. Once you pull up to the gate you may have to honk your horn to get the gate keepers attention. The entrance fee is 40 pesos per car and 40 pesos per passenger so be sure to take advantage of your trunk space to save a few pesos. The site itself is around 60 kilometers down one of the windiest, narrowest roads you will ever drive so plan on driving carefully and on about a hour to get to the site. Or you can drive like a maniac like I did, which was a lot of fun but definitely not recommended. But hey it was as rental car so what do I care?