Background: The substitution of hazardous chemicals with safer alternatives is an important objective in European chemical policy, but implementation has been slower than expected. We conduct a comprehensive analysis and comparison of the implementation of the substitution principle in European regulations for pesticides, biocides, and industrial chemicals. Specifically, we examine and compare the criteria and processes associated with the identification of candidates for substitution and the assessment of alternatives. Results: We find only minor differences in the criteria applied to identify candidates for substitution amongst pesticides, biocides, and industrial chemicals, but larger differences concerning the processes used. While all substances that are to be approved as a pesticide and biocide are systematically evaluated against the established criteria for substitution, the substitution process for industrial chemicals only focuses on those substances identified as substances of very high concern. The main reason candidates for substitution remain on the market is the lack of identified safer chemical alternatives and the insufficient consideration of non-chemical alternatives, caused, at least to a large extent, by the comparatively weak incentives provided by current regulations. Conclusions: The systematic approach for the identification of industrial substances of very high concern (SVHC) under ECHAs “Integrated Regulatory Strategy” is much welcome. However, no final conclusion on SVHC properties or the need for regulatory action has been drawn for approximately 90% of the REACH-registered substances, as often even basic hazard and exposure data are missing. Hence, at least a screening-level evaluation of SVHC properties should become a mandatory part of the substance registration under REACH. To reduce the risk of strategic behaviour in the search for alternatives to industrial chemicals identified as SVHC, a setup in which regulatory authorities play a larger role as information and knowledge brokers should be considered. Investments in innovation as well as improved sharing of information and a better distribution of the workloads amongst European authorities might also improve the identification of safer alternatives. However, without stronger incentives, making it more costly for companies to continue using hazardous substances relative to safer alternatives, initiatives to promote substitution are likely to have limited success.