Mycoplasma gallisepticum (MG) is an important avian pathogen that causes significant economic losses in the poultry industry. Surprisingly, the limited protection and adverse reactions caused by the vaccines, including live vaccines, bacterin-based (killed) vaccines, and recombinant viral vaccines is still a major concern. Mycoplasma gallisepticum strains vary in infectivity and virulence and infection may sometimes unapparent and goes undetected. Although extensive research has been carried out on the biology of this pathogen, information is lacking about the type of immune response that confers protection and selection of appropriate protective antigens and adjuvants. Regardless of numerous efforts focused on the development of safe and effective vaccine for the control of MG, the use of modern DNA vaccine technology selected in silico approaches for the use of conserved recombinant proteins may be a better choice for the preparation of novel effective vaccines. More research is needed to characterize and elucidate MG products modulating MG-host interactions. These products could be used as a reference for the preparation and development of vaccines to control MG infections in poultry flocks.