Several gene-expression-based reference laboratory tests are now available for prognostication of patients diagnosed with breast cancer. For clinical oncologists, it is important to understand the clinical contexts for which these assays were developed in order to use them properly. This Review is aimed at providing a conceptual and technical overview of the steps involved in the development of gene-expression profiling-based prognostic assays. MammaPrint and Oncotype DX, two widely utilized assays, are compared with respect to differences in the clinical contexts for their development, technologies used, and clinical utilities with the aim of providing a guide to clinical oncologists for utilization of these assays.