The first year, I ran in my fivefingers, I did so without socks. This hurt, especially on 15k+ runs. It also caused all sorts of problems, from painful calluses to blisters that refused to heal before my next run. After about a year, I came to the conclusion that it wasn't that my feet needed toughening up. A layer of fabric will always help in reducing the friction between shoes and skin. After I had finally bought a pair of toe-socks - which helped a great deal - I still got calluses on the sides of my feet during longer runs. Yet another year later, I decided to try and find some Engo patches.
In the words of Sherlock (the recent BBC incarnation), my blisters issue was a three-patch problem.