This research discusses the role of the baptism and infilling of the Holy Spirit in missions through a specific focus on Ghanaian Pentecostal Churches. Scripture, history, scholarly works, interviews, observations, ecumenical documents, as well as relevant documents of Ghanaian Pentecostal churches were used to study the issue under discussion. In order to achieve the objective for the topic chosen, the research also discusses some of the major factors that led to Pentecostalism in Ghana – i.e. the concern of the indigenes about their worldview not being addressed by the Western missionaries that came to serve in Ghana. In the desire of the then Ghanaian Christians to have their worldview addressed, they resorted first to the Pentecostalism initiated by the African Initiated Churches, and then to the current trend of Pentecostalism in Ghana. The findings reveal that, though one of the factors that has made Pentecostalism so acceptable to Ghanaians is the way it has addressed their worldview; Ghanaian Pentecostal Churches themselves are of the opinion that the role of the Holy Spirit is the major factor. Their argument is that, it takes the role of the Holy Spirit to convict a sinner of his or her sins and incorporate the person into the body of Christ. After this incorporation, the person needs to be continually filled with the Holy Spirit in order to be able to live according to the will of God. Furthermore, it is the Holy Spirit that also empowers believers to work both within and outside the church. This empowerment is manifested through the gifts that the Holy Spirit gives to believers – for both their personal edification and the perfection of the church. As believers operate in the gifts of the Holy Spirit, God works through them in the power of the Holy Spirit to fulfill the missio Dei. It was finally revealed that, although the Holy Spirit is the power behind mission, the human factor cannot be forgotten. With this in mind, it was argued that Ghanaian Pentecostal churches have put into place various missional approaches, to help them to effectively participate in the missio Dei. These missional approaches were therefore discussed in the light of the “five marks of mission” (i.e. Evangelism, discipleship, responding to the social needs of people through love, transforming the unjust structures of society and safe guarding the integrity of creation) and Krintzinger et al.’s holistic mission approach (i.e. kerygmatic, diaconal, fellowship and liturgical).