As basic principles to explain emergence of empathy in humans, this article proposes a theoretical framework of “bottom-up empathy” and “top-down empathy.” The former is driven by external stimuli and emerged on the basis of physical and autonomic properties of neural systems. The latter means processes to infer others’ intentions, thoughts, and emotions based on mental models which are maintained in cognitive systems. The bottom-up empathy can be realized by synchronization of spontaneous fluctuation of neural activity in brain regions including the inferior lateral prefrontal cortex and insula, among two or plural persons. The top-down empathy can be rooted in neural systems for the mentalizing or “theory of mind”, including the medial prefrontal cortex, superior temporal sulcus, temporal–parietal junction, and insula. Probably the insula which is an interface of the brain and body might be a key brain region which can connect the bottom-up empathy and top-down empathy. This theoretical framework might be useful to explore characteristics of human empathy and to apply the basic findings into real world phenomena.