Fewer than 10% of drugs entering Phase I reach approval—and even successful ones often leave value on the table due to early decisions. Big pharma can absorb these misses; biotech CEOs cannot. While biology and translation risks are real, much value loss is decisional, concentrated in a handful of critical choices that shape capital use, risk, and evidence quality. Advances in AI, biomarkers, and real-world data are also raising the bar for smarter, earlier decisions. This discussion will address getting those decisions right across five key inflection points: indication and population, target product profile and pivotal commitments, trial design and evidence strategy, market preparation and access, and commercial readiness.