1) What is matter made of?
2) Why is gravity so different from charge?
3) Why does time seem to flow in only one direction?
4) Where did all the antimatter go?
5) How does the chaos of fluid things result in the order of solid things?
6) What relates gravity and charge?
7) How did life evolve from lifeless matter?
8) What is the nature of consciousness?
There are any number of different lists of the great issues of science. For example, this list of 5 great issues of science includes all of the above questions.
A more recent 2018jun02 Mach article wonders more generally about the apparent lack of progress for physics over the last 48 or so years, but Mach seems to neglect the other sciences besides physics theories. Although there have been many successful measurements that have confirmed theories from before 1970, there have been no new predictions from new physics theories for 48 years.
In fact, many of the scientists interviewed in this article noted that physics seems to be in a quandry today. While physics publishes more papers than ever and runs ever greater missions of collective science, there do seem to be fewer new theories along with a massive amount of new data. One thing missing from this analysis is that there are in fact a large number of physics theories and yet there are no measurements to distinguish among these theories...or so it would seem.