For the last few years, the fourth industrial revolution, known as Industry 4.0, has been a hot topic among academics. Industry 4.0 literature involves researches presenting studies related to its different aspects including challenges, opportunities, implementation and adoption. However, a detailed study of challenges and barriers towards the Industry 4.0 implementation in manufacturing industries is missing. Hence, this paper aims to study and analyze the Industry 4.0 implementation challenges in manufacturing industries based on the expert opinions and the Interpretive Structural Modelling (ISM). The ISM analysis investigates the challenges in a structural base, finds the relationships between these challenges and finally shows how challenges affect each other to uncover the root cause triggering the other challenges. The industrial practitioners and managers can then take advantage of this analysis to know which challenge acts as the main barrier towards Industry 4.0 implementation and to be focused first in order to reach a solution.