Abstract Motivation: Many large genomes are getting sequenced nowadays. Biologists are eager to start microarray analysis taking advantage of all known genes of a species, but existing microarray design tools were very inefficient for large genomes. Also, many existing tools operate in a batch mode that does not assure best designs. Results: Picky is an efficient oligo microarray design tool for large genomes. Picky integrates novel computer science techniques and the best known nearest-neighbor parameters to quickly identify sequence similarities and estimate their hybridization properties. Oligos designed by Picky are computationally optimized to guarantee the best specificity, sensitivity and uniformity under the given design constrains. Picky can be used to design arrays for whole genomes, or for only a subset of genes. The latter can still be screened against a whole genome to attain the same quality as a whole genome array, thereby permitting low budget, pathway-specific experiments to be conducted with large genomes. Picky is the fastest oligo array design tool currently available to the public, requiring only a few hours to process large gene sets from rice, maize or human. Availability: Picky is independent of any external software to execute, is designed for non-programmers to easily operate through a graphical user interface, and is made available for all major computing platforms (e.g. Mac, Windows and Linux) at http://www.complex.iastate.edu. Supplementary information: A short paper detailing the probability analysis for Picky, a program that implements functions mentioned in the paper, and the output of the program are available online from the Publisher's website.