Mutant B-RAF is a critical oncogenic driver in melanoma, making it an attractive therapeutic target. However, the success of targeted therapy using B-RAF inhibitors, vemurafenib and dabrafenib, has been limited due to development of resistance, restricting their clinical efficacy. An a priori knowledge of resistance mechanisms to B-RAFi or any kinase inhibitor may lead to development of drugs that bypass the resistance thus improving clinical efficacy. In vitro cellular models are powerful systems that can be utilized to mimic and study resistance mechanisms. Mass spectrometry-based proteomics and phosphoproteomics is the method of choice to understand aberrations in protein levels and phosphorylation-based signalling in drug resistance. In this study, we employed a panel of B-RAF mutant melanoma cell lines to develop and systematically characterize B-RAFi resistant cells using exome sequencing, proteomics, and phosphoproteomics. Our datasets recapitulated intrinsic and acquired, genetic and non-genetic mechanisms of B-RAFi resistance that have been studied in patients who developed resistance to B-RAFi. In addition, we could identify potential therapeutic targets that can be targeted to overcome B-RAFi resistance. Overall, we demonstrate that in vitro systems interfaced with multi-omics analyses can be utilized not only to predict resistance mechanisms but also to identify putative therapeutic targets.