Swift growth in the use of LC-MS/MS for the analysis of drugs in biological matrices has been compelled by the need for timely and high-quality data at many stages in drug discovery and development process: from high throughput screening of drug candidates and rapid data generation for pre-clinical studies to almost real-time analysis of clinical samples. Prompt and rational method development, validation, and transfer play a pivotal role in achieving the goals of “faster, better, and cheaper” for pharmacokinetic studies since this could easily account for more than 50% of the time and labor resources for a moderate-sized project. Strategy for rational method development, validation and transfer has been largely kept as institutional knowledge but rarely appeared in literature. In this review article, strategies for developing and validating robust high throughput LC-MS/MS methods will be critically reviewed and discussed. Automated sample preparation, fast chromatography, minimization of matrix effects, and strategy of narrowing the gap between validation and incurred sample analysis are just a few topics covered in this review. Other interesting approaches for improving method efficiency and ruggedness such as direct injection SPE and liquid/liquid extracts as well as multiplexing of LC columns will also be discussed. Potential pitfalls during method development and validation are pointed out. At the end, the question “how fast is fast enough and how fast is too fast?” will be answered after considering all aspects of the method development and validation.