The One True Pairing (usually abbreviated as OTP) is the couple that a fan or group of fans prefers over all other 'ships. Canon and logic do not necessarily apply, and crossover OTPs are not uncommon.
The degrees to which this is taken varies wildly. It can mean anything from "I just like K2 best" to "I won't read Fan Fic that pairs Kyle and Kenny with anyone but each other", to the extreme "All the canon evidence that Stan and Cartman are not going to get together is a lie spread by the Kyman 'shippers, who must be stopped before their evil destroys the universe".
OTP Shipping Wars are notorious for heat and violence. The degree of fanaticism displayed for a particular OTP is usually proportional to their distance from the Official Couple and/or canonical evidence.
It is technically possible for a person to have multiple OTPs.
Some people refer to their favourite threesome ship by the similar term One True Threesome, or OT 3. Or really, "OT" appended with any number if they're even more ambitious with the number of people involved.
Often the term "OTP" is used sarcastically in parody of shipping, especially if it involves an unconventional pairing, or a character and their favorite food ("Cartman/Cheesy Poofs OTP"), etc. etc.