The modern pharmaceutical industry must be sustainable since (global) demand is greater than ever and its environmental footprint is massive. The purpose of this chapter is to introduce a range of novel methodologies for improving environmental sustainability and operational efficiency throughout the entire drug lifecycle. This chapter addresses the greener framework by reviewing the eco-design and drug life-cycle phases and emission reduction opportunities, as well as defining strategies for drugs with a low environmental footprint. The recommended approach to drug repositioning is that of a tiered nature, where the first steps in chemoinformatic and molecular modeling, being simple comparisons, do not consume resources or generate waste. This approach combines green medicinal chemistry with biologically sustainable supply chain practices to generate environmentally friendly, patient-healthy, and commercially viable medicines. This chapter urges academics, industry, and regulators to work together so that sustainability is embedded in the pharmaceutical domain: a sector that should serve current health needs while preserving environmental integrity for future generations.