In recent years, advances in experimental psychology have led to a better understanding in automatic, unconscious processes, referred to as attentional and approach biases amongst individuals with substance use disorders. Attentional biases refer to the relatively automatic tendencies for attention to be preferentially allocated towards substance-related cues. Whereas, approach bias refers to the relatively automatic behavioral tendencies of individuals to reach out to substance-related cues in their natural environment. While, several reviews confirm the existence of these biases, and the effectiveness of bias modification, the conduct of cognitive bias modification amongst substance-using individuals is not without its challenges. One of these is that cognitive biases, both attentional and approach biases, are not universally present; and several individual differences factors modulate the magnitude of the biases. Another challenge that investigators faced in their conduct of cognitive bias modification relates to the selection of the appropriate task for bias assessment and modification. Other challenges intrinsic to cognitive bias modification intervention relates to that of participant attrition, much like conventional psychotherapies. Negative findings, of the absence of biases at baseline, or the lack of effectiveness of bias modification have been reported in studies of cognitive bias modification. All these challenges could have an impact on bias assessment and modification. In this perspective paper, we will explore the literature surrounding each of these challenges and discuss potential measures that could be undertaken to mitigate these clinical and research challenges.