There aren't any major issues with ClickOnce you need to worry about, it does its thing really well. However you will run into a number of challenges to make it work smoothly for multiple clients.
By 'client' I presume you mean 'customer'? And each customer has n users who will each install your app?
You and MAGE will need to become friends. Why? Ideally you want to create one published build (that has passed all tests on your build machine and has passed QA), from this build you want to create a separate deployment for each client. To do so requires changing, at the very least, the InstallUrl and UpdateUrl MsBuild values, because it is a different web dir for each client.
As soon as you make these changes ClickOnce will no longer install the app because one or more of the files have been modified. At this point you may use MAGE to regenerate the application manifest (e.g. myApp.exe.manifest) and THEN the deployment manifest (e.g. myApp.application). One issue I found with doing this was you need to change the "Application Files" directory to "ApplicationFiles".
We are in the process of doing exactly this, take one published build then create a couple of dozen 'deployments' of that build for separate sites, each of which has different configuration info such as web service urls.
It takes quite a bit of time to get it working properly and then more time to automate it...if I was to say one 'must do' it would be make sure you automate the process with batch files or a command line app...doesn't matter HOW you automate it just make sure it is.
Good luck!