Development of childhood asthma is complex with a strong interaction of genetic, epigenetic, and environmental factors. Ultimately, it is critical how the immune system of a child responds to these influences and whether effective strategies for a balanced and healthy immune maturation can be assured. Pregnancy and early childhood are particularly susceptible for exogenous influences due to the developing nature of a child's immune system. While endogenous influences such as family history and the genetic background are immutable, epigenetic regulations can be modulated by both heredity and environmental exposures. Prenatal influences such as a mother's nutrition, smoking, or infections influence the complex interplay of innate and adaptive immune regulation as well as peri-and postnatal influences including mode of delivery. Early in life, induction and continuous training of healthy maturation include balanced innate immunity (e.g., via innate lymphoid cells) and an equilibrium of T-cell subpopulations (e.g., via regulatory T cells) to counterregulate potential pro-inflammatory or exuberant immune reactions. Later in childhood, rather compensatory immune mechanisms are required to modulate deviant regulation of a child's already primed immune trajectory. The specific effects of exogenous and endogenous influences on a child's maturing immune system are summarized in this review, and its importance and potential intervention for early prevention and treatment strategies are delineated.