We use a variety of experimental results to illustrate issues and challenges involved in the sampling and characterization of pharmaceutical mixtures. Accurate and reliable characterization of granular mixtures is hindered by both the complexity of granular systems and the lack of validated and reliable sampling technology and techniques. Both sampling tools and sampling protocols are critically important for accurate characterization. Using cohesive and free-flowing powders and four thief probe designs, we reveal a large potential for extremely misleading results as well as severe disturbance of the granular bed. We also discuss results from several experiments designed to test the validity of various sampling protocols by varying parameters such as sampling location and frequency of sampling. These experiments illustrate the importance of effective sampling procedures to achieve the best and most efficient results.