© Springer Science+Business Media New York 2013. All rights are reserved. The provision of human tissues to support biomedical research faces many challenges, including some misconceptions by investigators of some of the issues involved in obtaining human tissues for research. This chapter is to aid investigators in understanding some of the limitations faced by biorepositories in the provision of human tissues to support research. This chapter also will be useful to sites that are considering establishing a human tissue biorepository. Challenges currently facing human tissue biorepositories include a general decrease in the sizes of many tumors and a great decrease in the availability of metastatic lesions with both these challenges due to improved approaches to the imaging of tumors as well as metastases. The availability of appropriate tissues to study neoplastic lesions also has been greatly reduced for some cancers such as breast by the increasing use of neoadjuvant therapy which may decrease the size of primary and metastatic lesions, differentially affect cellular populations in cancers, and prevent their accurate staging. Another challenge is the increasing use of fine needle aspirations in tissue diagnoses. The availability of adequate resources to support tissue biorepositories has always been a challenge which is complicated by ill-advised, unnecessary proposed changes in governmental regulations acting as unfunded mandates affecting biorepository operations. Biorepositories are attempting to meet these challenges by introducing new methods of sampling tissues such as nitrocellulose blotting and by adapting methods so that paraffin embedded tissues can be used; also, additional tissues specifically to support research can be obtained directly from consented patients.