To gain insight into macromolecule function, one must investigate the structure. The first step in RNA folding is stable base pairing that leads to a secondary structure. As RNA structure formation is of hierarchical nature, secondary structure is the basis for the tertiary fold that produces the functional structure. Especially for RNAs, structure determination by experimental means is an intricate and expensive task. Computational RNA structure prediction is therefore an invaluable tool for biologists. Comparative structure prediction is considered the most reliable approach for computational RNA structure prediction. Single sequence structure prediction is always limited by the accuracy of the underlying folding model. Three main streams have been identified for comparative RNA secondary structure prediction: (i) predict a structure from a pre-computed sequence alignment; (ii) simultaneously compute an alignment and a structure and (iii) alignment-free methods (Gardner and Giegerich, 2004) .