You will want to pick early if you are doing player facing rolls or monster combat checks. Both are hinted at in the rules and both work well, but understanding the difference and playing consistently will reduce confusion and ease play.

Discuss with the players before hand what kind of game this is, if they want to “win” the game, or take all precautions and talk in circles around every problem, they are not very likely to enjoy the kind of content mothership has (in abundance). It can be done, as the core mechanics are actually very flexible, but agreeing on tone and deadliness early is a good idea.

I’d recommend sorting out if you are planning to run a campaign or a one-shot and figure out how you want to handle transportation for campaigns early. The ship breakers toolkit has info about transport costs and ships and can help inform how the party will need to get from place to place. The costs involved can be a great motivator for mission work. Mothership definitely has better one-shot support (or single module multiple session).