Breast cancer stands as the most prevalent cancer in women globally, and contributes to the highest percentage of mortality due to cancer-related deaths in women. Paclitaxel (PTX) is heavily relied on as a frontline chemotherapy drug in breast cancer treatment, especially in advanced metastatic cancer. Generation of resistance to PTX often derails clinical management and adversely affects patient outcomes. Understanding the molecular mechanism of PTX resistance is necessary to device methods to aid in overcoming the resistance. Recent studies exploring the mechanism of development of PTX resistance have led to unveiling of a range novel therapeutic targets. PTX resistance pathways that involve major regulatory proteins/RNAs like RNF8/Twist/ROR1, TLR, ErbB3/ErbB2, BRCA1- IRIS, MENA, LIN9, MiRNA, FoxM1 and IRAK1 have expanded the complexity of resistance mechanisms, and brought newer insights into the development of drug targets. These resistance-related targets can be dealt with synthetic/natural therapeutics in combination with PTX. The present review encompasses the recent understanding of PTX resistance mechanisms in breast cancer and possible therapeutic combinations to overcome resistance.