The identification of structural genetic alterations, including DNA amplifications, deletions, and loss of heterozygosity (LOH), using single nucleotide polymorphism (SNP) microarrays has provided important insights into the pathogenesis of a number of hematologic malignancies. Currently available SNP arrays comprise over a million SNP and copy number oligonucleotide probes that interrogate the genome at sub-kilobase resolution. The accurate detection of DNA copy number abnormalities and LOH is critically dependent on the use of high-quality DNA, the use of matched reference samples wherever possible, optimal normalization of raw microarray data, and computational algorithms to detect copy number alterations sensitively and robustly. This chapter provides methods and guidelines for preparing samples, processing and analyzing data, and validation of novel lesions. Specific examples are provided for Affymetrix SNP arrays in acute lymphoblastic leukemia.