 What does it mean to pray in the Holy Spirit? But you, beloved, building yourselves up in your most holy faith and praying in the Holy Spirit. To pray in the Spirit is to desire an agreement with heaven, to speak aloud those petitions which originate from the will of the Father. True prayer in the Spirit begins in union with God. Praying in the Holy Spirit is praying in harmony with the will of the Holy Spirit, with the guidance of the Holy Spirit and in the power of the Holy Spirit.