We recently had several clients whose exchange servers went offline for seemingly no apparent reason. The servers were up and there were no connection or permissions issues, but we kept getting a strange error in the logs.
Error: Unable to initialize the Information Store service because the clocks on the client and server are skewed. This may be caused by a time change either in the client or the server, and may require a reboot of that computer. Verify that your domain is properly configured and is currently online.
After investigation, we found that the Vmhost running the exchange server did not have the correct time set up. We changed the time on the host (we actually enabled NTP to match the domain controller), and rebooted the exchange server. The exchange server came up and the infostore started without error. Everything was then fine in the world again.
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