In my mind, the next big challenge is to integrate the work on macro (mostly growth, trade, and finance) with the work on micro (mostly health, education, and evaluation). A few people are working in that intersection, but not nearly enough in my view. The micro economists face the challenge of demonstrating that their work can say something about economy-wide growth patterns and differentials--the strongest determinant of poverty patterns in the world. Meanwhile, macro types have to develop evidence that passes the microeconomists' more demanding requirements.
See also the papers for Northeast Universities Development Consortium Conference to get a flavor.
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