If you see the following error in your Exchange 2003, 2007, or 2010 queue, there are three things you should do to troubleshoot the problem:

451 4.4.0 Primary target IP address responded with: “421 4.2.1 Unable to connect.” Attempted failover to alternate host, but that did not succeed. Either there are no alternate hosts, or delivery failed to all alternate hosts.

Below are the three items you need to check:

1. Test the connection by sending an email through command line.  This is MUCH easier than it soundsOpen a CMD command prompt on any PC or ServerType telnet <DestinationEmailServerName>25 and press enter.

   Type helo yourdomain.com and enter.

   Type mail from: yourname@yourdomain.com and enter.

   Type rcpt to: recipient@remotedomain.com and enter.

   Type data and enter.

   Type subject: test and enter.

   Type test and enter.

   Type . and enter to quit the session

   If you do not see any errors, this proves the problem is with your server and not with the recipients server.

2. Test to ensure the domain in question has an Mail Exchanger (MX record) configured properly:Open a CMD command prompt on any PC or ServerType nslookup

   Type set q=mx

   Type <remote email domain name>

   If you see the name of a server, then they have an MX record

3. Use web tools to troubleshoot odd problems:- Check your INBOUND and OUTBOUND SMTP settings using Microsofts fantastic: www.testexchangeconnectivity.com
   - Use the MXToolBox Supertool www.mxtoolbox.com/SuperTool.aspx
   - Make sure your rDNS (reverse DNS) is setup is correct: remote.12dt.com/lookup.php

If all this fails, post your question on a forum like http://social.microsoft.com/Forums/en-US/partnermsgexchange/thread/8d41844f-cc28-4a4b-9463-fd5e53392830 and read articles like http://blogs.technet.com/b/messaging_with_communications/archive/2011/04/22/how-to-manage-exchange-2010-message-queues.aspx