The fungal component of microbiota, known as the mycobiome, inhabits different body niches such as the skin and the gastrointestinal, respiratory, and genitourinary tracts. Much information has been gained on the bacterial component of the human microbiota, but the mycobiome has remained somewhat elusive due to its sparsity, variability, susceptibility to environmental factors (e.g., early life colonization, diet, or pharmacological treatments), and the specific in vitro culture challenges. Functionally, the mycobiome is known to play a role in modulating innate and adaptive immune responses by interacting with microorganisms and immune cells. The latter elicits anti-fungal responses via the recognition of specific fungal cell-wall components (e.g., β-1,3-glucan, mannan, and chitin) by immune system receptors. These receptors then regulate the activation and differentiation of many innate and adaptive immune cells including mucocutaneous cell barriers, macrophages, neutrophils, dendritic cells, natural killer cells, innate-like lymphoid cells, and T and B lymphocytes. Mycobiome disruptions have been correlated with various diseases affecting mostly the brain, lungs, liver and pancreas. This work reviews our current knowledge on the mycobiome, focusing on its composition, research challenges, conditioning factors, interactions with the bacteriome and the immune system, and the known mycobiome alterations associated with disease.