The immune system is collection of cells, tissues and molecules that protects the body from pathogenic microbes and toxins. It is divided into two parts namely innate or natural immune response and adoptive immune response. Natural immune response is more aggressive and does not have memory. Adoptive immune response is silent but when gets activated, creates barrier to neutralize or eliminate foreign body or microbes. Adoptive immune response can be humoral or cell-mediated response. This chapter covers the indications for investigations, male infertility, natural killer cells, and immunomodulation therapy. Natural killer (NK) cells resemble CD8+ T cells in many phenotypic, functional and morphological. NK cells are inhibited by binding to self-HLA and will therefore kill cells that lack self HLA class I molecules—known as the missing self-response. Immunomodulation therapy is a new concept and, based on it, it is reasonable to think that the use of different lines of immune therapies (e.g. intralipid, antipaternal immunization, intravenous immunoglobulin, prednisolone, tumor necrosis factor-α blockers), to reduce NK cell activity in infertile women has to be reconsidered because the scientific principle of maternofetal tolerance has been misunderstood.