Abstract This qualitative study investigates effectuation and causation as two opposing decisionmaking modes leading to opportunity creation and recognition. Prior literature posits that effectuation is linked to opportunity creation when the venture׳s future is highly uncertain and causation to opportunity recognition when the entrepreneur perceives risk rather than uncertainty. However, such a linear approach towards opportunity generation offers limited explanation as to how entrepreneurs decide to either create or search for entrepreneurial opportunities. This limitation becomes particularly apparent in the highly uncertain context of the biotechnology industry, where entrepreneurial decision-making processes iterate over long periods of time. To address this gap, we employ the embedded case study method to investigate 30 decisions made by three scientist-entrepreneurs commercializing platform biotechnology inventions. We inductively derive a model of entrepreneurial decision-making, which connects the environment to decision-making mode and opportunity generation. Our evidence reveals the iterative nature of opportunity generation and of decision-making modes as entrepreneurs respond to their evolving environment and to the level of regulatory and funding constraint, such that entrepreneurs can shift from effectuation to causation, remain in one particular mode, or adopt a combination mode. We also illustrate that effectuation does not always lead to opportunity creation.