SPOCTOPUS is a method for combined prediction of signal peptides and membrane protein topology, suitable for genome-scale studies. Its objective is to minimize false predictions of transmembrane regions as signal peptides and vice versa. We provide a description of the SPOCTOPUS algorithm together with a performance evaluation where SPOCTOPUS compares favorably with state-of-the-art methods for signal peptide and topology predictions. AVAILABILITY: SPOCTOPUS is available as a web server and both the source code and benchmark data are available for download at http://octopus.cbr.su.se/