Enhanced metastasis and disease recurrence accounts for the high mortality rates associated with cancer. The process of Epithelial-Mesenchymal Transition (EMT) contributes towards the augmentation of cancer invasiveness along with the gain of stem-like and the subsequent drug-resistant behavior. Apart from the well-established transcriptional regulation, EMT is also controlled post-transcriptionally by virtue of alternative splicing (AS). Numerous genes including Fibroblast Growth Factor receptor (FGFR) as well as CD44 are differentially spliced during this trans-differentiation process which, in turn, governs cancer progression. These splicing alterations are controlled by various splicing factors including ESRP, RBFOX2 as well as hnRNPs. Here, we have depicted the mechanisms governing the splice isoform switching of FGFR and CD44. Moreover, the role of the splice variants generated by AS of these gene transcripts in modulating the metastatic potential and stem-like/chemoresistant behavior of cancer cells has also been highlighted. Additionally, the involvement of splicing factors in regulating EMT/invasiveness along with drug-resistance as well as the metabolic properties of the cells has been emphasized. Tumorigenesis is accompanied by a remodeling of the cellular splicing profile generating diverse protein isoforms which, in turn, control the cancer-associated hallmarks. Therefore, we have also briefly discussed about a wide variety of genes which are differentially spliced in the tumor cells and promote cancer progression. We have also outlined different strategies for targeting the tumor-associated splicing events which have shown promising results and therefore this approach might be useful in developing therapies to reduce cancer aggressiveness in a more specific manner.