A few timeouts can improve email server performance, but most shouldn't be adjusted.
On I/O-bound machines, throttling connections based on load limits usually isn't as effective as it might at first seem.
Significant performance gains cannot generally be realized by making sendmail less security conscious than it is by default.
Features such as STARTTLS and mail filters are wonderful from a utility standpoint, but they may have significant performance implications.
A FallbackMX host can help relieve the load from email servers sending messages out to the Internet.
A Spillover host can queue up messages coming from the Internet into an organization if the organization's primary machines cannot respond due to load problems or a network outage. Of the two types of hosts, deploying a FallbackMX host generally has the larger overall performance impact.
When possible, it's generally more cost-effective and more scalable to distribute a given load over several smaller servers than to have one big server handle it.