I'm leaving this open-ended, there's no specific criteria for responses.
I'm interested in both your list and the reasons why. Submitting your list before reading other's contributions would be preferred.
Optionally: who is (or isn't) successfully addressing them. Individuals, organizations, companies, governments, other. How and/or why not?
Heck -- what would be necessary to make our current, planet-bound society sustainable in the long term?
How can we address the massive inequality in the world without massive loss of life? Counting both the possibility of violent confrontation and the possibility of millions of lives being cut short or degraded by poverty.
How can the problems of global warming be corrected or at least coped with? Again -- without massive loss of life in the process.
Is it possible to reliably extend an individual human life beyond the span of a century or so?
How can we build institutions, or at least ideals, which can effect positive change over a period of hundreds or thousands of years?
Various groups are working on these problems, including governments, corporations and NGOs. I don't really think any of them are doing a great job.