Chemoresistance is one of the major hurdles in cancer treatment leading to recurrence of cancer and affects the overall survival of patients. Cancer chemoresistance can be associated with various phenomena including modulation of vital cellular pathways. Unrevealing these alterations could provide a better understanding of chemoresistance and assist in the identification of new targets to overcome it. Recent advances in the field of proteomics and metabolomics have substantially helped in the identification of potential targets for chemoresistance in various cancers. This review highlights the potential of proteomics and metabolomics research to explore the putative targets associated with cancer chemoresistance with a special focus on Multiple Myeloma (MM). MM is a type of hematological malignancy which constitutes about 13% of all blood cell cancers. The therapeutic advancements for MM have increased the median overall survival rate to over 3-fold in the last one and half decade. Although in recent times, significant improvements in the overall survival rate of MM are achieved, MM remains an incurable disease with unpredictable refractory mechanisms. In spite of therapeutic advances, chemoresistance thrives to be a major hurdle in the treatment of multiple myeloma which demands a better understanding of chemoresistance. In this review, we have attempted to highlight the potential applications of proteomics and metabolomics research in the understanding of chemoresistance in MM.