The present invention provides methods for optimizing oligonucleotide hybridization probes for use in basic and clinical research. Specifically, the invention involves hybridizing serially diluted genomic sample to the oligonucleotide probes on the array, such that a signal intensity is produced for each of the probes; computationally identifying optimized probes which exhibit signal intensities that correspond to the serial dilutions of genomic sample and are reproducibly strong relative to non-optimized probes.