Structural genomics has the goal of obtaining useful, three-dimensional mod
els of all proteins by a combination of experimental structure determinatio
n and comparative model building. We evaluate different strategies for opti
mizing information return on effort. The strategy that maximizes structural
coverage requires about seven times fewer structure determinations compare
d with the strategy in which targets are selected at random, With a choice
of reasonable model quality and the goal of 90% coverage, we extrapolate th
e estimate of the total effort of structural genomics. It would take simila
r to 16,000 carefully selected structure determinations to construct useful
atomic models for the vast majority of all proteins. In practice, unless t
here is global coordination of target selection, the total effort will like
ly increase by a factor of three. The task can be accomplished within a dec
ade provided that selection of targets is highly coordinated and significan
t funding is available.