With the advent of next-generation DNA sequencing machines, there is an increasing need for the development of computational tools that can anchor accurately and expediently the millions of generated short DNA sequences (or reads) onto the genomes of target organisms. In this work, we describe ‘Q-Pick’, a new and efficient method for solving this problem. Q-Pick allows the rapid identification and anchoring of such reads with possible wildcards in large genomic databases, while guaranteeing completeness of results and efficiency of operation. Q-Pick requires very spartan memory and computational resources, and is trivially amenable to SIMD implementation; it can also be easily extended to handle longer reads, e.g. 75-mers or longer. Our experiments indicate that Q-Pick can anchor millions of distinct short reads against both strands of a mammalian genome in seconds, using a single-core computer processor.