Several chemicals in consumer products are subject to binding or voluntary phase-out agreements that are based on international treaties such as the Stockholm Convention on Persistent Organic Pollutants or on regulatory frameworks such as the European Union's Registration, Evaluation, Authorization and Restriction of Chemicals (REACH). To facilitate a phase-out process, alternatives assessment is commonly applied as an emerging approach to identifying chemicals (or materials, processes, and behavior changes) serving as substitutes. Polybrominated diphenyl ethers (PBDEs), long-chain poly- and perfluorinated alkyl substances (PFASs), and polychlorinated biphenyls (PCBs) are well-known cases of chemicals where substitution processes can be studied. Currently, there are various challenges in assessing, evaluating and effectively introducing chemical alternatives. These challenges are mainly related to similarity in chemical structures and, hence, similar hazard profiles between phase-out and substitute chemicals, leading to a rather incremental than fundamental substitution. A hampered phase-out process, the lack of implementing Green Chemistry principles in chemicals design, and lack of Sustainable Chemistry aspects in industrial processes design constitute additional challenges. We illustrate the various challenges in the process of phasing out and successfully substituting hazardous chemicals in consumer products and provide guiding principles for addressing these challenges. We propose an integrated approach of all stakeholders involved toward more fundamental and function-based substitution by greener and more sustainable alternatives. Our recommendations finally constitute a starting point for identifying further research needs and for improving current alternatives assessment practice.