Isn't it the same as before? If 4gb of data was too big because you had 2gb of RAM, then the methods used at that time are the same you would apply for a 500gb dataset that can't fit in a 250gb RAM machine, right?
New issues appear when you have to analyze 2Tb with a 32gb RAM machine, but when the order of difference is the same, the issues and thus the answers are the same as before?