Today's mechanistic-Empirical (M-E) pavement design involves comprehensive, computerized packages. However, this also brings with it major challenges of calibration and validation, determination of appropriate input values, resource needs for implementation and balancing complexity and comprehensiveness with understandability and practicality. This paper starts with a brief summary of the evolution of M-E design, and lists a number of available, computerized analytical solutions. It then describes the basic inputs and outcomes that should be incorporated in a design procedure, as well as considerations in choosing an appropriate M-E procedure. Two case examples of challenges in implementing an M-E procedure are presented. The first involves a simplified, equivalent two-layer elastic model where calibration consisted of two stages, the first based on an extensive data base of field performance, and the second based on an expert panel's design estimates in a matrix of factor combinations. The second example involves AASHTO's new Mechanistic-Empirical Pavement Design Guide (MEPDG) where the hierarchical levels of design inputs are first described, and a summary description of a recent sensitivity analysis of the input factors in the rutting and fatigue models is then provided. Finally, the paper suggests some future challenges and opportunities could include comparative sensitivity or interactions of factors analysis for the MEPDG as well as documentation and dissemination of calibration and validation results. Additionally, there is the potential of moving to more fundamental analytical techniques, such as application of micromechanics.