Just as one example, I thought I'd share my strategy:

I need 300K Air Canada points a year and 100-150,000 points on other airlines for overseas trips. I book hotels on Priceline.

So I:

a) Aggressively churn Amex cards and go after signup bonuses, threshold bonuses, referral bonuses, etc. I also buy Amex points from co-workers, although this is very unusual for FTers.
b) Sign up in both my wife's name and mine for cards from AA, UA, US, DL, and Chase. My goal is that each summer when I have to book one or two overseas tickets, to have enough points to book one or sometimes two business class tickets on whichever alliance has the best schedules.
c) Manage the signup process so I can meet the spend requirements and sometimes spend requirements for bonuses, using some of the spending tricks listed elsewhere in this forum.
d) I do not bother with hotel cards, cards for primarily domestic airlines (like Southwest or JetBlue), or cashback or quasi-cash cards (cards where you get points whose use is tied to the price of tickets you buy). The incremental value isn't worth the time and effort.
e) Occasionally I have applied for a card solely for trade value; i.e. someone approaches me and offers me, say, 20000 Amex points if I sign up for the Amadeus Air (made-up name) miles card. Not often though.

There is definitely a point of diminishing returns, a trade-off between the effort involved and the gain from that effort.