Cancer is an uncontrolled expansion of atypical cells in the body. These unusual cells are labelled as cancerous or malignant cells. Melphalan, an anticancer drug which is imperatively recognized under the class of alkylating agents. It exhibits broad spectrum antitumor activity, as observed in ovarian cancer, breast cancer, etc. However, it is mainly utilized in the management of multiple myeloma. Several studies across the globe suggest that resistance to melphalan is the major concern that leads to relapsed myeloma. In the present paper, several pivotal approaches to compensate resistance associated with melphalan have been discussed. Numerous chemical and formulation developments concerning melphalan to enhance its salient characteristics and targeted profile have also been portrayed. The rationale of the current article also summarizes the recent analytical methods, structure-activity relationship, pharmacokinetics, interactions, potential adverse effects along with medicinal updates of melphalan. Special attention is also laid on their synthetic developments viz. melphalan derivatives, conjugates and prodrugs along with encouraging insights and research findings. [Display omitted] • Present paper describes conjugates and prodrugs of melphalan with improved anticancer activity and pharmacokinetic profile. • Various analytical methods for the estimation of melphalan have been discussed. • Melphalan resistance and methods to overcome resistance have been summarized. • Present paper will be helpful for the researchers working in the area of anticancer evaluation of melphalan derivatives. [ABSTRACT FROM AUTHOR]