Over the past 50 years, advances in molecular and developmental biology have outstripped a truly integrated synthesis of evolutionary theory. So for my money the most significant breakthrough will come in the form of retro-fitting these advances with issues still hanging on, in some instances, from the 19th century. They include the importance of isolation in evolution; the degree to which genetic and morphological change are correlated with speciation; and the role and importance of extinctions in shaping subsequent evolution.
At stake is a more complete understanding of the environmental context in which natural selection operates, and the relative roles of the physical and biological environment versus "selfish genes" in driving the process.
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