Current nursing literature recognizes the need to honor the concept of ambiguity. Nurses experience uncertainty with handling or honoring complexity and ambiguity when confronted with times of struggle. Traditional models of care fall short as patients and families define their expectations of the healthcare system. Nurses bear witness to the discomfort caused by the unknown in their daily practice. They are challenged to address their feelings, unsure of what to anticipate, what to say, or how to respond to their patients. Uncertainty diminishes the opportunity for meaningful dialogue between nurses and other people. Nurses attempting to ease the discomfort of ambiguity by providing patients or families with reassurance, offering advice on how to fix problems, or avoiding talking about situations often express dissatisfaction. Nurses should be invited to explore ambiguity and seek understanding through dialogue and nursing knowledge. Encouraging nurses to define the meaningfulness in nursing practice that embraces human science theory will help relieve some of the ambiguity that exists in current practice. This article will explore the concept of ambiguity, highlight how nursing theory based on human science can support practice, and propose recommendations for practice.