Chronic fatigue syndrome (CFS) is a long-term and debilitating condition that regards as a neurological disease. Its symptoms include profound physical and mental fatigue (characteristically made worse by exertion), muscle and joint pain, disturbed sleep, and both concentration and memory problems. CFS is a kind of human stress-related disorders that are characterized by alterations in hypothalamic-pituitary-adrenal (HPA) axis activity. Investigation of abnormal activity of the HPA axis in various neurological and neuropsychiatric disorders can date back at least 60 years, and its relation to CFS had been reported in the early 1990s. This chapter further disseminated updated evidence for disruption of HPA function in CFS, with the explanation on the relationship between cytokines and HPA activities. Moreover, very limited literature had addressed the importance of rehabilitation to them. This chapter addresses this gap by sharing a pilot rehabilitation outcome on a single-blinded randomized control trial with a parallel group experimental design in the application of activity scheduling (AS) program of occupational therapy for a group of community-dwelling older adults with CFS. The primary objective is to study the outcome of physical functioning of individual participants. The second objective is to study the outcome of AS on impact of caring role through assessing individual caregivers' perceived burden in care. The third objective is to study the time that needed in taking care; individuals' perception of enjoyment and achievement in their participated activities will be evaluated. There was a significant effect of AS on the physical functioning of participants as measured by Functional Independence Measure (FIM), as the primary outcome measure, in experimental group, with Wilk's λ = 0.72, F (2,57) = 18.75, p < 0.001. Moreover, in secondary outcome measures, there is a significant decrease in the impact of caring role as reflected by their perceived burden as measured by the Chinese Zarit Burden Interview (CZBI) in caring for experimental group, with Wilk's λ = 0.72, F (2,97) = 18.75, p < 0.001. Another study set out to examine the effect of time on caring activities for those recruited couples in AS group. There was significant effect of AS on caring activities with Wilk's λ = 0.71, F (2,97) = 12.47, p < 0.001. With proper coaching and regular facilitation regarding AS, activity participation in older adults with CFS can be greatly enhanced. Behavioral intervention, such as AS, can supplement therapeutic treatment or may lead to decline in CFS symptoms.