All righrs reserved. Several nucleic acids hybridization-based approaches, such as microarray, competitive genomic, and Southern or Northern blot hybridization, have become popular tools for specialists in biochemistry and in biomedicine, and are now in routine use. However, the potential of in-solution nucleic acids hybridization-based experimental techniques seems to be underestimated now. Examples are subtractive hybridization (SH), which allows one to efficiently find differences in genomic DNAs or in cDNA samples; coincidence cloning (CC), which, on the contrary, makes it possible to identify sequences that are present in all the samples under comparison; cDNA normalization, which is used for the smoothing of rare and frequent transcript content in cDNA libraries; and TILLING approach, which has demonstrated its great potential for the reverse genetics studies. Finally, several techniques are aimed at the large-scale recovery of DNA polymorphisms, including single nucleotide polymorphisms (SNPs). This book will focus on the above-mentioned and other recent developments in the area of nucleic acids hybridization, including attempts to improve its specificity. In this introductory chapter, I have tried to briefly characterize the current state of the art in in-solution nucleic acids hybridization techniques, and to define their major principles and applications. The advantages and shortcomings of these techniques will be discussed here.