Oil the occasion of the 50th anniversary of the Journal of Structural Biology, we review some of the major advances that have taken place in molecular and cellular structural biology over this timeframe and consider some current trends, as well as promising new directions. While the primary experimental techniques of X-ray diffraction, electron microscopy and NMR spectroscopy continue to improve and other powerful new techniques have come on-line, it appears that the most comprehensive analyses of large, dynamic, macromolecular machines will rely on integrated combinations of different methodologies, viz. "hybrid approaches". The same prospect applies to the challenge of integrating observations of isolated macromolecules with data pertaining to their distributions and interaction networks in living cells. Looking ahead, computation in its diverse aspects may be expected to assume an increasingly important role in structural biology, as the prediction of molecular structures, the computation of dynamic properties, and quantitative time-resolved models of intracellular molecular populations (structural systems biology) move towards functional maturity. (C) 2008 Elsevier Inc. All rights reserved.