A16z's foundational belief is that founders, not hired "professional CEOs," should lead their companies long-term. The firm is structured as a network of specialists to provide founders with the knowledge and connections they lack, enabling them to grow into the CEO role and succeed.

A CEO's primary role differs fundamentally based on company type. In an asset-centric biotech, the CEO must act as a hands-on program manager, micromanaging execution. In a platform company, the CEO must be deeply embedded in the science to predict and leverage the technology's long-term trajectory.

The expectation for venture capitalists has shifted. Founders no longer just want finance professionals; they demand investors who have direct operational experience and have been "in the trenches" of building a company. This change reflects a move towards more hands-on, value-add investing.

The ultimate differentiator for CEOs over decades isn't just product, but their skill as a capital allocator. Once a company generates cash, the CEO's job shifts to investing it wisely through M&A, R&D, and buybacks, a skill few are trained for but the best master.

Experience taught Herb Wagner that great leaders consistently surprise on the upside. He now weights leadership quality far more heavily, assessing CEOs not by interviews or charisma, but by their verifiable track record and through trusted backchannel references who have worked with them directly.

First-time CEOs often change their entire strategy after talking to a few investors. This is a red flag signaling a lack of conviction. Investors want to see a CEO who listens and evolves but ultimately sticks to their core, well-researched beliefs, especially when faced with disarming questions.

Successor CEOs cannot replicate the founder's all-encompassing "working memory" of the company and its products. Recognizing this is key. The role must shift from knowing everything to building a cohesive team and focusing on the few strategic decisions only the CEO can make.

An engineering background provides strong first-principles thinking for a CEO. However, to effectively scale a company, engineer founders must elevate their identity to become a specialist in all business functions—sales, policy, recruiting—not just product.

Luba Greenwood argues that unlike in tech, many biotech CEOs lack P&L experience. In today's cash-constrained market, CEOs need to be able to build financial models and understand finance deeply to be effective, a skill she personally developed after transitioning from law and science.