We report the first evaluation of Constraint Satisfaction as a computational framework for solving closest string problems. We show that careful consideration of symbol occurrences can provide search heuristics that provide several orders of magnitude speedup at and above the optimal distance. We also report the first analysis and evaluation – using any technique – of the computational difficulties involved in the identification of all closest strings for a given input set. We describe algorithms for web-scale distributed solution of closest string problems, both purely based on AI backtrack search and also hybrid numeric-AI methods.