Superior-quality human tissues are required to support many types of biomedical research. To be useful optimally in supporting research, not only must these tissues be accurately diagnosed, but also the specific aliquots of tissue supplied to investigators must be accurately described as part of the quality control analysis of the tissue. Tissues should be collected, processed, and stored uniformly. Some tissues are provided to investigators from tissue banks for which tissues have been collected and processed according to standard operating procedures (SOPs) of the tissue bank. Other tissues provided to support research are collected and processed according to SOPs modified to meet investigator needs and requirements, i.e., prospective collection/processing. These different models of tissue collection require different goals, designs, and SOPs. The objectives of tissue repositories also vary based on the types of tissues provided (e.g., fresh tissue aliquots, fixed paraffin-embedded tissue, paraffin tissue sections, etc.) and how the tissues are to be used in research. For example, the potential use of tissues affects the need for extensive annotation of the specimen including both clinical information (e.g., clinical outcomes) and demographics. Specifically, if the tissues are to be used for extraction of proteins or basic studies of disease processes, less clinical information, if any, may be needed than if the tissues are to be used for the correlation of an aspect of the disease process with clinical outcome or response to a specific therapy. In this review, we describe, based on our experience, the major issues that should be addressed in designing and establishing a tissue repository.