ESyPred3D: Prediction of proteins 3D structures. Motivation: Homology or comparative modeling is currently the most accurate method to predict the three-dimensional structure of proteins. It generally consists in four steps: (1) databanks searching to identify the structural homolog, (2) target–template alignment, (3) model building and optimization, and (4) model evaluation. The target–template alignment step is generally accepted as the most critical step in homology modeling. Results: We present here ESyPred3D, a new automated homology modeling program. The method gets benefit of the increased alignment performances of a new alignment strategy. Alignments are obtained by combining, weighting and screening the results of several multiple alignment programs. The final three-dimensional structure is build using the modeling package MODELLER. ESyPred3D was tested on 13 targets in the CASP4 experiment (Critical Assessment of Techniques for Proteins Structural Prediction). Our alignment strategy obtains better results compared to PSI-BLAST alignments and ESyPred3D alignments are among the most accurate compared to those of participants having used the same template. Availability: ESyPred3D is available through its web site at http://www.fundp.ac.be/urbm/bioinfo/esypred/