The development of high-resolution microarray-based comparative genomic hybridization (aCGH), using cDNA, bacterial artificial chromosome (BAC) and oligonucleotide probes, is providing tremendous opportunities for translational research by facilitating detailed analysis of entire cancer genomes in a single experiment. However, this technology will only fulfil its promise if studies incorporating aCGH are designed with a full understanding of its current limitations and the strategies available to circumvent them. While there have been several excellent reviews on the current status of this technology, there is currently very little guidance available regarding the appropriate design of experiments incorporating aCGH (including the strengths and weaknesses of each platform), and how best to combine the results obtained from aCGH with other 'omic' technologies, including gene expression. In this review, we present the key design issues that need to be considered in order to optimize aCGH studies, including sample selection, the definition of appropriate experimental objectives, arguments for and against the various microarray platforms that are currently available, and methods for data validation and integration. It is envisaged that future well-designed aCGH studies will enhance our understanding of the genetic basis of cancer, and lead to the identification of novel predictive and prognostic cancer biomarkers, as well as molecular therapeutic targets in cancer.