HHsenser is the first server to offer exhaustive intermediate profile searches, which it combines with pairwise comparison of hidden Markov models. Starting from a single protein sequence or a multiple alignment, it can iteratively explore whole superfamilies, producing few or no false positives. The output is a multiple alignment of all detected homologs. HHsenser's sensitivity should make it a useful tool for evolutionary studies. It may also aid applications that rely on diverse multiple sequence alignments as input, such as homology-based structure and function prediction, or the determination of functional residues by conservation scoring and functional subtyping. HHsenser can be accessed at http://hhsenser. tuebingen.mpg.de/. It has also been integrated into our structure and function prediction server HHpred (http://hhpred.tuebingen.mpg.de/) to improve predictions for near-singleton sequences.