After the outbreak in French Polynesia “the great Zika virus (ZIKV) explosive pandemic” occurred in 2015, and reports that ZIKV was linked to other diseases, especially neurological complications such as Guillain-Barré syndrome (GBS), also burst in almost every continent, thereby turning into an international concern. In South America, the highest incidence occurred in Venezuela with approximately 680 cases of GBS after ZIKV infection. Currently, the main roots of this association remain unknown. In this regard, is thought that the immune system plays a central role in such association through the host protection or even improving ZIKV establishment and progression. Non-neutralizing auto-antibodies, the complement system, self-reactive T cells, inflammation, the “cytokine storm”, prior exposures to other arboviruses such as dengue virus and chikungunya virus, the age and genetic susceptibility of the patient, and the biology of the vector are the main determinant factors, which perhaps, are involved in the pathological relationship: ZIKV and GBS. On the other hand, it is need more multidisciplinary studies to provide means to develop effective therapeutics against this new global health threat that represents an emerging danger that can increase again and trigger other neurological disorders.