It is a constant challenge to provide timely bioanalytical support for the evaluation of drug-like properties and PK/PD profiles for the ever-increasing numbers of new chemical entities in a cost-effective manner. While technological advancement in various aspects of LC-MS/MS analysis has significantly improved bioanalytical efficiency, a number of simple sample reduction strategies can be employed to reduce the number of samples requiring analysis, and as a result increase the bioanalytical productivity without deploying additional instruments. In this review, advantages and precautions of common sample reduction strategies, such as sample pooling and cassette dosing, are discussed. In addition, other approaches such as reducing calibration standards and eliminating over-the-curve sample reanalysis will also be discussed. Taken together, these approaches can significantly increase the capacity and throughput of discovery bioanalysis without adding instruments, and are viable means to enhance the overall productivity of the bioanalytical laboratory.