Interaction with the immune system is one of the most recently established nonclassic effects of vitamin D (VitD). For many years, this was considered to be limited to granulomatous diseases in which synthesis of active 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) or calcitriol is known to be increased. However, recent reports have supported a role for 1,25(OH)2D3 in promoting normal function of the innate and adaptive immune systems. Crucially, these effects seem to be mediated not only by the endocrine function of circulating calcitriol but also via paracrine (i.e., refers to effects to adjacent or nearby cells) and/or intracrine activity (i.e., refers to a hormone acting inside a cell) of 1,25(OH)2D3 from its precursor 25(OH)D3, the main circulating metabolite of VitD. The ability of this vitamin to influence human immune responsiveness seems to be highly dependent on the 25(OH)D3 status of individuals and may lead to aberrant response to infection or even to autoimmunity in those who are lacking VitD. The potential health significance of this has been underlined by increasing awareness of impaired status in populations across the globe. This review will examine the current understanding of how VitD status may modulate the responsiveness of the human immune system. Furthermore, we discuss how it may play a role in host resistance to common pathogens and how effective is its supplementation for treatment or prevention of infectious diseases in humans.