Methods, reagents and kits are disclosed for selecting target-specific oligonucleotide probes, which may be used in analyzing a target nucleic acid sequence. In one aspect the present invention is directed to selecting a set of target-specific oligonucleotide probes. A cross-hybridization oligonucleotide probe is identified based on a candidate target-specific oligonucleotide probe for the target nucleic acid sequence. The cross-hybridization oligonucleotide probe measures the extent of occurrence of a cross-hybridization event having a predetermined probability. Cross-hybridization results are determined employing the cross-hybridization oligonucleotide probe and the target-specific oligonucleotide probe. The target-specific oligonucleotide probe is selected or rejected for the set based on the cross-hybridization results.