Disclaimer: These answers are based on my two favorite saves (Westbrook and Xalavdor families) that I've mentioned a lot here on the forums. This isn't how I always play my game though. It varies from save to save
One, Two or More Sims?
One sim but then branch off as their kids age up.
One or More Active Households?
As my sim's kids age up and move out, I rotate between the households. In other saves, I do enjoy rotational play though. I found that by having a connections (no matter how small) between sims helps with rotational play. It could be just they live in he same neighborhood (or apartment building if playing in San Myshuno).
Which World to Live In?
It depends on what I think my sim would want. Emilia Westbrook started in Windenburg, but Orion Xalvador lived in Strangerville. He's an alien and his ship crash-landed in Strangerville.
Which Worlds Connect and Which Do Not?
I don't really play with any worlds closed off. I let my sims travel freely between the worlds. I do like having Sulani and Mt. Komorebi as vacation worlds though.
Occult Play or Realistic?
It depends on my mood. For the most part I lean toward realistic.
If Occult Play, Which? (All or Exclude Some?)
For some reason in my game, I gravitate toward aliens. I don't always play them though. It depends on my mood but none are excluded if I play occults.
Lifespan; Down to Details (One Sim Year = ? )
I play on Normal lifespan modified by MCCC (2 or 3 extra days per lifestage). I consider one sim year to be based on seasons rather than sim ages. More on that in Seasons question.
Skill Difficulty Adjustment (to Match Lifespan)
I don't do any skills adjustments.
Length of Seasons, consider Holidays
I typically do 28 day seasons. So one sim year is 28x4=112 days. But I've also used LittleMsSam's 21 day seasons mod.
For holidays, I have the default ones as well as...
-- Founder's day, which is the first day of the first season I play in. For example, if I start my save in Spring, Founder's day would be the first day of Spring the next time Spring comes around. It's to commemorate my founding sim. The traditions are similar to Memorial day in the US.
-- Summer vacation is usually halfway through the season and lasts a week. I usually send my sims to Sulani for a week. Each day has water activities or grilling.
-- Winter vacation is usually the days between WinterFest (Christmas) and New Years Eve. I send my sims to Mt. Komrebi. The tradtions are winter-related activities.
-- Other holidays depend on the save.
No Mods, Select Few or Multiple Mods?
Mods, mods, and more mods. I do not play my game without MCCC, Wonderful Whims, Lumpinous Relationships & Pregnancy Overhaul, Bienchen's Traits Overhaul, Whims Overhaul, MissyHissy's Custom Wants mod, and Ky-E's Lifetime Aspirations (adopted by NeedCoffee4That).
Money Cheat/s, or No?
For the most part, no money cheats. When moving sims to New houses, I may cheat if my sims are a few 1000 simoleons short, but I make my sims earn their stuff.
Other important considerations?
-- I start with a loose backstory and let the game (and mods) decide my sims' fate. I don't restart or quit without saving if anything happens. The only time I quit without saving is if my sim dies straight out of CAS, which has never happened to me.
If a sim gets pregnant from abduction, I raise the baby, no sending to homeworld.
-- Wonderful Whims has an attraction feature, and I only allow my sims to marry sims they find Extremely Attractive. Now that we have Compatibility from Growing Together, I also only allow sims they find Extremely Attractive and have at least Good Compatibility with. My sims can date whomever they want but can only marry the aforementioned sims. It makes it harder for them to find love, which in my opinion is a bit too easy. It also makes me take things slower instead of picking a random sim on the street.
-- When moving to New house, my sims take their furniture with them (apart from counters, plumbing, and lights...things that wouldn't be easy to remove in real life). The house they move to only has those things until I put their stuff in.
When rotating between households:
-- I rotate every Sunday and Wednesday at 6am. Aging for non-played sims is on/off when a new rotation starts.
-- Neighborhood stories are turned off for Played households. They're on but customized per non-played household. For example, only households with elders can retire. For single sim households, I turn off their stories in case I want them to marry one of my played Sims. Sometimes I'll move them to played households for reserve to stop Neighborhood stories.
Not all saves:
--No repeat aspirations (except family aspirations). Gen 2 can't repeat my founders' aspiration. This makes me really think about other aspirations and keeps me from doing the same ones. Same thing with traits. It gets me out of my comfort zone.
-- Sims must complete a degree.
The two saves I mentioned above have been my favorites of any sims game. I noticed that when I let the game guide me, I have a deeper connection to my sims, which makes me want to continue their lives. I like when my sims have obstacles to overcome (i.e unexpected pregnancy, divorce, etc.). Real life isn't easy so my sims' lives aren't. One of my Westbrook family sims couldn't have children (disabled in CAS) so she adopted. I rarely use features in the way they're intended. I used the stay over feature for one sim (not in the saves mentioned here) to spend the weekend with his affair partner.
This is super long but I hope it gives you some ideas.