The current review illustrates the method development and validation of capillary electrophoresis (CE) from experiences of the author research group. Various examples including drug monitoring, pharmaceutical, and natural product analyses are described. The author emphasizes that no specific CE condition is applicable for all problems. Analytes’ physicochemical properties (e.g., solubility, dissociation constant, polarity, absorptivity, etc.) and their stability are major consideration. Sample matrices (e.g., biological fluid and tissues, foods, medicinal plants, etc.) can usually complicate an analysis and should be accounted for before a method is developed. Consequently, sample pretreatment/preparation procedures have to be carefully optimized as well. Successes in CE separation involve adjustments of both chemical (e.g., background electrolyte concentrations and pH, organic solvents, electro-osmotic flow modifiers, additives, etc.) and instrumental (e.g., sample loading techniques, temperature, voltage, capillary dimension, detectors, etc.) factors. Optimization of these factors can be achieved by univariate approach or statistical experimental design. The final optimum CE condition should be justified by acceptable analytical parameters (e.g., resolution, tailing factor, number of theoretical plate, total analysis time, etc.). Method validation is a follow up process, which should be carried out according to the predetermined protocol and criteria of performance. These criteria normally include specificity, linearity and range, accuracy, precision, and robustness. BGE and sample solution stability may be required in certain cases and system suitability should be carried out for method transfer.