This is a bit hard of a question to answer, since you included Leverage in the tags, which includes Cortex Plus as a result. Both Smallville and Leverage use Cortex Plus as a base, which isn't really the same system, but more of a design language that influences the design of a specific system.
The previous Cortex systems are something like Savage Worlds, and honestly they were mechanically so boring that I couldn't tell you the differences between Serenity or Supernatural. I can, however tell you some of the differences between original Cortex and Smallville and Leverage.
Original Cortex follows a standard attribute + skill generic system. Smallville instead uses a combination of relationships and drives, so your chance of success in any action depends on how important the person involved is, and how important the key issue is to you. Smallville also has multiple types of stress, including fatigue, injury, and anger. It's a lot more interesting damage wise than previous systems. Smallville also makes heavy use of plot points to influence actions, and also to use super abilities. Plot points are acquired when inconvenient or bad but interesting things happen to you, which rather matches why Clark always runs into trouble with Kryptonite before getting out.
Leverage goes a bit back, having a combination of attributes + roles. So you have the 6 attributes, and 5 roles, and you use whichever attribute and role combination is appropriate. Sometimes more than one is, and you'd roll more than just 2 dice. Leverage has no damage system of any kind. You just have degrees of success or failure, and then continue until you succeed overall. If something goes wrong, you get a flashback to show how you planned for that all along, or had a plan B at least, and get to introduce that to get yourself out of a situation that you failed because of bad luck with the dice.
There's going to be a Hacking Cortex Plus supplement released at some point (this year I would assume), that would answer questions about rules changes that are applicable to both Leverage and Smallville, they may also be to some degree applicable to original Cortex, but I couldn't say until it actually gets released.