I will try to hit this the best I can for you.

If you are in a single server scenario and NEVER care to do anything else in the near term (say next 12 months), and have memory on the system running the site to handle your estimated persistent data load then System.Web.Caching used AS-IS should be fine.

Here are things to consider if you move beyond any of the above restrictions:

1. If you think you may change caching strategies during the life of the system - You will want to put a simple pattern around your caching API calls. This will allow for easier upgrades or changes to other caching options in the future. Since caching api's tend to be build for that cache system and there is no standardization you want to do this to insulate yourself for big regressive changes across your code base when you switch from System.Web.Caching to say AppFabric caching.

2. If you plan to have a web farm with more than 1 box serving the same application and you are not using sticky sessions. In this case you will want to move to a external cache store like AppFabric in order to give all systems in the farm access to the same data. Even with sticky sessions you may want AppFabric as you can use it to decrease common data loads and opens up the possibility to move to stateless web applications later.

3. If you need very tight control over caching (such as TTL, expiration, sliding rules, update rules etc) then you may want to look at a more robust caching system than plain System.Web.Caching.

4. If you want to do things like pre-load data on application start or even have backend systems capable of updating cache data that the front end system is using live then you will want something more powerful and flexible than System.Web.Caching.

I am sure there are some more I can think of given the time. If you would like a suggestion on what you can use please give me a somewhat high level idea of your application and what you are trying to do.

A bit about me(doing this to be taken somewhat seriously): 15+ year enterprise systems engineer and architect using Microsoft development tools and technologies since 1994. Currently working at a financial company with a 3-million user system based on MVC3 and .NET 4 with AppFabric in a web farm environment so this stuff is kinda at the top of my head right now.