Let me start out by saying that I know a lot of people will find this post upsetting, and probably will completely dismiss the idea of ever wanting to include "sad" things in TS3, but I would like to explore the idea nonetheless...
1.) I would like to have an option (that could be turned on and off in the gameplay options) for Sims to randomly develop terminal diseases (such as cancer). At times I find the whole concept of "here's how long your Sim will live, so you know how much fun they can have in their lifetime". I would like to have the idea of a tragically shortened lifespan, and the urgency to do and see things while they are still able to do so. Call me morbid, but I believe this could add a whole new dimension of story-telling to the game. Your Sim could start by having strange symptoms, and if they choose to go to the hospital they could be told that they have a terminal disease and should start preparing for the end. Maybe your sick Sim could gain 3x - 5x the normal experience points for fulfilling wishes during this last period of their life. They could work on a will and file it at City Hall. There are many things that could tie in with this.
2.) Why don't we have "little people" Sims, or Sims with disfigured bone structures? Why can't we have Sims with cerebral palsy? (again, this option could be toggled on or off). I rather like the idea of not knowing with 100% certainty that my pregnant Sim is going to give birth to a perfectly healthy Sim child with no genetic anomalies whatsoever. I like the idea of surprises and challenges!
3.) Speaking of challenges, could we maybe have Sims with special needs (developmental disabilities, physical disabilities)? We could have Sims who are intellectually challenged... Sims with autism... maybe even Sims in wheelchairs! Your adult Sim could have a wish to adopt a child Sim with special needs, and they could receive a stipend from the Sim government to help with expenses. Your special Sim child could have obstacles to overcome in everyday life, and their parent or guardian would be with them every step of the way. When a Sim with special needs fulfills a wish (even one that seems small by a "typical" Sim's standards), they could gain big points along with a boost to their mood, and perhaps they could have a lifetime wish such as "Live Independently in My Own Home" or "Get a Full-Time Job". If your Sim with special needs dies with a fulfilled lifetime wish, there could be a random chance that your city names a vocational center or group home after them, in honor of their perseverance in living a fulfilling life and reaching for their dreams.
I want to see more diversity and uncertainty in the life cycle of the Sims. It would provide more challenges, more excitement and wonderful stories. Opinions, please.