Electrostatic discharge (ESD) protection is a grand design challenge for complex ICs in advanced technologies. ESD simulation is indispensable to guide ESD protection designs. However, no existing ESD simulation methods may accurately predict ESD protection designs in a universal manner due to various inherent limitations. TCAD-based ESD simulation is very useful for ESD protection designs. Transmission line pulse (TLP) and very fast TLP (VFTLP) are widely used to evaluate human body model (HBM) and charged device model (CDM) ESD protection designs, which provide rich details for calibrating TCAD ESD simulation for design prediction and validation. Using various ESD protection devices fabricated in 28nm CMOS and 45nm SOI CMOS technologies, a comprehensive experimental and simulation study finds that the ESD stimuli used in TCAD ESD design simulation have profound impacts on many subtle ESD protection behaviors, particularly in comparison with ESD testing. This study cautions against over-interpretation of TCAD ESD simulation results, obtained using any specific ESD stimulus, attempting to accurately predict practical ESD protection designs. A mixed-mode multiple-stimuli ESD simulation method is therefore developed to address the ESD stimulus induced ESD performance variation, hence offering a technique to achieve ESD protection design prediction.