We want to run the majority of our mail (inbound and outbound) through a third-party service provider. We also want to keep an SMTP server running onsite that will be used with existing automated senders tied to internal projects. A colleague thought there might be problems (getting spam blacklisted, for instance) with operating multiple SMTP servers for one domain. Is there some additional setup (for the domain/nameservice, etc.) that needs to be done to make this work?
3 Answers
To expound on what Halfgaar has said:
You can operate multiple ourgoing SMTP servers and what you probably want to do is to set up an SPF record in your public DNS namespace that identifies all SMTP servers that are authorized to send email for your domain. Also set up appropriate A and PTR records for any SMTP server sending email for your domain. This is not a guarantess that you won't be blacklisted, but it will go along way to making sure you're not. Make sure that any MX records set up for the domain only point to the third party email provider as you don't want any inbound email going to the onsite SMTP server. Also make sure that any email sent from the onsite SMTP server goes out with reply to addresses that are valid so that replies are sent to legitimate recipients at the third party email provider.

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I'm not really sure I understand what you mean, but here's my two cents:
You can easily use different outgoing SMTP servers, as long as their hostnames resolve properly (otherwise it is a spam suspect).
As for incoming, you can set multiple MX records on a domain, but it is not configurable which one is used; you can only set multiple servers for fall over. In other words, for a domain example.com, you have to add MX records specifying which servers to use whenever you send mail to something@example.com.

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MX records are to tell the world where to deliver email destined for one's domain name - Incoming. Kyle's question is about multiple SMTP serverrs for _outgoing_ delivery. – icelava Jan 13 '10 at 14:44
In addition to previous answers from joeqwerty, you should also make sure of the following:
- Your ISP will allow you to make SMTP connections to the rest of the world. Most ISPs will only allow TCP port 25 traffic to/from their SMTP servers. If that's the case, you can set your internal SMTP server to relay all email through your ISPs email server.
- Make sure the IP that your internal server is using is added to the DNS SPF record for your domain.

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