We have used many different support systems and have found that WHMC's Built in system and Ubersmith are the best, which one you use depends on the project.
You'd be surprised at how 'easy' it is to use , honestly, though I have to say I'm not a huge fan of their markdown implementation. This should have been done far better.
I noticed everyone is really suggesting WHMCS. Which is a great choice. I recommend Box Billing. Great software, looks fantastic and is way cheaper than WHMCS.
WHMCS is one of the Best business automation tool to maintain and control all your clients details. Its a all-in-one tool which handles billing, administration, sales, abuse, technical support and other options.
Unless you want to sale premium support you would surely settle for the free inbuild WHMCS version. Definitely lucks a few things but works perfectly well for most support tasks.
Figured I would also add SupportPal (formerly ArcticDesk) to this thread. SP is built by the folks behind LicensePal and seems to be a great cheap product.
It appears to be more of a Kayako 3 type product in terms of feature set so not as advanced but at the same time not significantly cheaper than Kayako 4.
We really like HostBill, as it integrates all of your automation, with a very good ticket system and live chat. Live chat and ticket system has macros (pre-written answers for common questions) and the ability to link a knowledge base (also included) article.
While the 'best' anything is going to be subjective (personal preference), selecting a helpdesk that's continually buggy and continues to stall development is not really the wisest choice for the 'best option'.
I do agree that WHMCS needs some helpdesk work, however it's getting there, especially with improvements made in 6.3
I prefer to use WHMCS system, the user only need to log in to one system for billing and support. Customers don't like to have to log in on 2 different systems.