In 15%-20% of breast cancers, human epidermal growth factor receptor 2 (HER2) is overexpressed. Part of HER2 is shed into the circulation, where it can be measured in serum as S-HER2. Although many studies have tried to establish the clinical usefulness of S-HER2, S-HER2 has not yet found its place in clinical practice because large prospective trials have been missing. We present our own recent work to provide a suggestion of the clinical use of S-HER2. A total of 540 patients were followed up after primary surgery. The sensitivity of detection of recurrence in tissue HER2-positive patients was 69% and the positive predictive value was 47% using a cutoff value of 15 μg/L. Further, we have shown that the S-HER2 value reflects the effect of targeted treatment with trastuzumab. An increase in S-HER2 was correlated with progression of disease in 40 out of 44 clinical courses, whereas a decrease in S-HER2 was correlated to no progression or regression in 20 out of 21 courses. We propose to include S-HER2 in the clinical follow-up after primary surgery of tissue HER2-positive breast cancer patients to detect recurrence. We suggest a prospective randomized trial on the individualized, tailored therapy of these patients using S-HER2 as an indicator of the need to investigate recurrence.