Finding the longest common subsequence (LCS) of multiple strings is an NP-hard problem, with many applications in the areas of bioinformatics and computational genomics. Although significant efforts have been made to address the problem and its special cases, the increasing complexity and size of biological data require more efficient methods applicable to an arbitrary number of strings. In this paper, a novel search algorithm, MLCS-A*, is presented for the general case of multiple LCS (or

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... problems. MLCS-A* is a variant of the A* algorithm. It maximizes a new heuristic estimate of the LCS in each search step so that the longest common subsequence can be found. As a natural extension of MLCS-A*, a fast algorithm, MLCS-APP, is also proposed to deal with large volume of biological data for which finding a LCS within reasonable time is impossible. The benchmark test shows that MLCS-APP is able to extract common subsequences close to the optimal ones and that MLCS-APP significantly outperforms existing heuristic approaches. When applied to 8 protein domain families, MLCS-APP produced more accurate results than existing multiple sequence alignment methods.