Active pharmaceutical ingredients (APIs), their metabolites, and transformation products (TPs) occur globally in the environment. They pose a risk to both environmental and human health. These alarming circumstances highlight the strong need for efficient measures, which is also reflected in EU strategies on sustainable chemicals and on pharmaceuticals in the environment. The design of APIs for mineralization in the environment according to the concept Benign by Design (BbD) is a promising approach to tackle this challenge. However, its implementation into the industrial API discovery process has not been discussed yet. To stimulate such a discussion and to better understand the applicability and limitations of this approach, the generic API discovery process is reviewed, including procedure, principles, and paradigms based on publicly available information. In addition to the concept of BbD itself, workflow scenarios such as de novo design and re-design are presented to provide a better understanding of its feasibility. Bringing these aspects together, we conclude that the optimization phase within drug discovery seems to be the most appropriate place to implement environmental considerations. At this early stage, costs are low and the potential impact of design and structural variation on the outcome is high. We found that pharmacological parameters required for application are sometimes even in line with biodegradability in the environment, since the conditions in the human body and the environment differ. However, the effects of optimizing pharmacological parameters such as toxicity and stability on environmental biodegradability of APIs must be considered together with design rules for biodegradability. Understanding the feasibility of BbD can mitigate the concerns pointed out by stakeholders and encourage them to invest in research and development, as well as support pharmaceutical companies to be prepared for upcoming regulations, since the aforementioned EU strategies announce further political regulations. We found also that successful implementation of BbD depends on the availability of suitable tools and methods as well as on incentives for research and development within constructive collaboration of industry, academia, and authorities.