Research conducted over the past few decades has made significant strides towards illuminating the role of spirituality during serious illness. We know spirituality is integral to patient and family lives as a framework for meaning-making, coping and decision-making. When spiritual needs are met, quality of life and hospice utilization are higher and costs are lower. However, while the evidence base is growing, in quantity and rigor, the field lacks gold standard approaches to definitions, measurement and assessment. To move forward, we must improve our evidence base with regard to 1) What are the definitions of spirituality and religion, and identifying key domains of those constructs 2) What is the impact of those domains on key health care outcomes; 3) What are the unique issues associated with research design? 4) How do we best assess spiritual needs and spiritual well-being? And 5) What do we know about interventions to address spiritual and existential care distress and well-being? This paper presents a discussion of our evidence base to date with regard to these key issues. It also offers priorities for improving the evidence base of spirituality and palliative care, so that this key aspect of patient and family experience is more fully understood and met with comprehensive and rigorously approaches to care.