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In this chapter, I survey the literature concerning selected metaphysical, epistemological, and ethical issues surrounding the intersection of spirituality and religion with medicine. The metaphysical issues concern what constitutes spirituality and its distinction from religion, especially with respect to medical research and practice; the nature of the causal relationship, particularly in mechanistic terms, between spirituality and clinical outcomes; and, the presuppositions animating clinical studies. The epistemological issues pertain to empirical evidence from clinical trials. The main issue is whether the evidence from these trials justifies an impact of spirituality and religion on health and clinical outcomes. The ethical issues involve how best to incorporate spirituality and religion into clinical practice, if they should be incorporated at all. Finally, the fundamental philosophical issue addressed in this chapter is whether the intersection of spirituality and religion with medicine has led to a humanized medicine that achieves medicine’s primary goal of relieving or reducing human suffering associated with illness.