The treatment of connective tissue disease (CTD) and CTD-related intractable diseases (CTD-IDs) currently depends on the use of steroid therapy. Approximately 20 years have passed since the approval of infliximab for rheumatoid arthritis in 2003. Since then, several biological therapeutics have been marketed and adapted for many CTDs and CTD-IDs other than rheumatoid arthritis. Although conventional treatment for patients with these diseases is rarely used because of their poor prognosis, these cases may benefit from biological therapeutics. However, choosing biological therapeutics is difficult because they have different target molecules compared with conventional therapeutics. In this review, we address the current situation of biological therapeutics for CTD-IDs including Behcet's disease, psoriatic arthritis, ankylosing spondylitis, anti-neutrophil cytoplasmic antibody-related arthritis, and adult Still's disease, as well as the choice of biological therapeutics in clinical practice.