This research explores an entrepreneurial decision-making process utilizing effectuation and forward sensmaking mechanisms which help determine an entrepreneur’s contingency decisions. Using a case study approach, we investigate the evolution of three small biotech ventures from the start of the venture, featuring entrepreneurs’ responses to market uncertainty over a period of 10 to 20 years. Assessment of qualitative interviews with founders and CEOs demonstrates that, initially, each company began in effectuation mode and evolves as entrepreneurs re-evaluate the use of limited resources to achieve what they can. Over time, however, sensemaking is invoked whenever external information signals/conflicts arise. Decision making processes in this study illustrate the interplay between entrepreneurs’ ability to manage limited resources and their interpretation of circumstantial events which resulted in changed leadership, directions of product development as well as organizational transformation.