A great deal of effort has been expended to develop accurate means of determining the properties of synthetic polymers using matrix-assisted laser desorption/ionization (MALDI) time-of-flight (TOF) mass spectrometry (MS). Many studies have focused on the importance of sample pre-treatment to obtain accurate analysis results. This review discusses the history of synthetic polymer characterization and highlights several applications of MALDI-TOF MS that recognize the importance of pre-treatment technologies. The subject area is of significance in the field of analytical chemistry, especially for users of the MALDI technique. Since the 2000s, many such technologies have been developed that feature improved methods and conditions, including solvent-free systems. In addition, the recent diversification of matrix types and the development of carbon-based matrix materials are described herein together with the current status and future directions of MALDI-TOF MS hardware and software development. We provide a summary of processes used for obtaining the best analytical results with synthetic polymeric materials using MALDI-TOF MS.