Firmware Configuration is very important, it basically tells Simplify3D what "flavor" of G-Code to make and what kind of X3G file to make (if necessary). This is set automatically by the software through the Configuration Assistant. However,when you have multiple printers you switch back-and-forth from, you may not be going through the Configuration Assistant every time you switch, which means you should probably ensure your firmware Configuration is right.
For Sailfish style machines
For RepRap style machines
As long as your properly set to RepRap style for a RepRap printer, you shouldn't have an issue. If you are set to the wrong Firmware Configuration you might notice your bed not waiting to heat up, fans not turning on, and tool-head switches not going through.
for MakerBot/Sailfish style machines (5th Gen MakerBots use RepRap Firmware Configuration)
Having the correct profile is important, but with MakerBot/Saiffish Firmware Configuration, the X3G setting the Machine Profile is really important!
For instance a common occurrence of wrong Machine Profile for MakerBot style printers, If you're using a Replicator 1-dual style printer, (FF Creator/CreatorPro,Wanhao Duplicator, PowerSpec, etc), but have it set on the default Replicator 2 profile you'll have the following symptoms:
Your heated bed won't work. (Replicator 2 doesn't have a heated bed)
You won't be able to use your left extruder. (Replicator 2 doesn't have a left extruder)
Your parts will be about 7% too small. (Replicator 2 uses different Steps-Per-MM values)
Example of practical use
For instance, if you use a FlashForge Creator Pro printer and a custom delta machine:
FlashForge Creator Pro-- MakerBot/Sailfish firmware with Replicator 1-dual extruder selected under the X3G tab
Custom Delta Machine-- RepRap firmware
When switching process settings from one to the other, it's very important to also go in to your Firmware Configuration and set that as well, otherwise you'll have a whole host of problems.
Conclusion
This generally applies to people with more than one printer, since single printer users can traditionally use the Configuration Assistant on the printer they have the first time through the software, and that will set the Firmware Configuration. However, if you're constantly switching printers, and are a printing enthusiast then it's vital to know this!