Fat soluble vitamers (FSV) are several biochemically diverse micronutrients essential for healthy development, growth, metabolism, and cell regulation. We cannot synthesize FSV completely or at the required concentrations. Deficiency or excess of FSV can result in many health problems. Plasma is the most accessible sample matrix for the quantification of FSV. However, due to its complexity and other analytical challenges (e.g., FSV sensitivity to light, oxygen, heat, pH, chemical heterogeneity, standard availability), developing a method for the simultaneous quantification of multiple FSV at physiological concentrations has been challenging. In this systematic review, we examine the parameters and criteria used in existing Liquid Chromatography with tandem Mass Spectrometry (LC-MS/MS) methods for FSV quantification to the extraction method, chromatographic resolution, matrix effects, and method validation as critical to a sensitive and robust method. We conclude that the final FSV method sensitivity is predominantly based on aforementioned criteria and future method development using LC-MS/MS will benefit from the application of this systematic review.