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Monitoring of CML patients while on therapy is vitally important and ENL has come up with specific guidelines for the same. Since we are currently talking about operational cure, this review shall focus on evaluating the emerging data to optimize response. This requires attention to all outstanding controversial issues. Only careful, accurate and regular monitoring with specific attention to grey areas will help us select first line therapy, decide when to discontinue TKIs and also move to second line TKIs in a timely manner.