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Previous research has investigated portfolio decisions as individually discrete decisions. In this research, however, we find that portfolio decision-making can only be adequately addressed if it is considered as an integrated system of processes. Using data from four diverse cases, we develop a general framework for how new product development portfolio decisions are made in firms. According to the findings from these cases, the objective of a firm’s portfolio decision-making processes should be to achieve a portfolio mindset to focus effort on the right projects, and to be agile in decision-making about the portfolio. On the one hand, three domain-based decision input generating processes lead to evidence-based portfolio decision-making. In addition, organizational politics may result in power-based portfolio decision-making while managerial intuition may lead to opinion-based decision-making. Firm cultural factors, including trust, collective ambition, and leadership style, influence how these evidence-, power-, and opinion-based processes are combined into a whole, and whether the firm’s processes are more rational and objectively made, or more politically and intuitively made.