Soluble CD14 (sCD14) is a part of innate immunity that has been implicated in many diseases, including allergic diseases. However, many influencing factors and confounders, including gender-gene-environment interactions, may complicate interpretations of the observed associations to allergic diseases. In this paper, we review current literature describing the functions of sCD14 and its associations with common (recurrent) infections and with allergic diseases. Because sCD14 is involved with immunologic responses to infections, and exposure to microbial compounds is debated as a protective or a trigger factor for allergy development, these factors-which include genotypes, gender, age, microbial agents (from the environment and infection), and tobacco smoke-cannot be assessed independently. We conclude that confounding effects are important and must be considered to understand the role of sCD14 in allergic development.