There are no serious issues with ClickOnce that you need to worry about; this is really good. However, you will encounter a number of problems to make it work smoothly for multiple clients.
By "client" I assume that you mean "client"? And each client has n users who will each install your application?
You and MAGE should be friends. What for? Ideally, you want to create one published assembly (which passed all the tests on your assembly machine and passed QA), from this assembly you want to create a separate deployment for each client. This requires at least changing the values of InstallUrl and UpdateUrl MsBuild, because this is a different web directory for each client.
Once you make these changes, ClickOnce will no longer install the application because one or more files have been changed. At this point, you can use MAGE to regenerate the application manifest (e.g. myApp.exe.manifest) and THEN the deployment manifest (e.g. myApp.application). One of the problems I ran into was that you need to change the Application Files directory to ApplicationFiles.
We do just that, take one published assembly, then create dozens of “deployments” of this assembly for individual sites, each of which has different configuration information, such as web service URLs.
It takes quite a lot of time to make it work properly, and then more time to automate it ... if I said what needs to be done, this will guarantee automation of the process with batch files or the line app command ... does not values HOW do you automate it, just make sure that it is.
Good luck