The present study is attempted to compare modern approaches for predicting protein domain boundaries and to define new prediction strategies. Here, we refer to the exercise named CASP7, organized in 2006, for which both predictions and experimental data are available on-line (http://www.predictioncenter.org/casp7/Casp7.html). In this manuscript, several tools, designed for predicting domain boundaries on the basis of the amino acid sequence, will be compared to the real domain architecture. The analysis of these data allows one to answer the following basic questions: i) Is it possible to predict, with the presently available bioinformatics tools, if a protein is made by a single domain or if it contains more than one domain? ii) What is the statistical significance of the available predictions? iii) How accurately can the domain boundaries be predicted in the cases where the presently available bioinformatics predictions work well?