Connective tissue diseases such as scleroderma frequently show an insidious onset. In their early stages a diagnosis of a specific CTD is hard to make, and the disorder may then be designated as "undifferentiated CTD." Raynaud's phenomenon (RP) is the first symptom in many cases and may precede the disease for many years. RP, however, is a common finding in the population, especially in young females. Thus, only a minority of patients with RP will develop a CTD. For reason of prognosis and early diagnosis and to get more insight in the initial pathophysiological processes, it is important to know which patients with RP will develop or are already evolving into a CTD. Patients referred to the clinician because of RP frequently (24-40%) show signs or symptoms of CTD, especially of scleroderma. Pulmonary function disturbances and esophageal hypomotility are asymptomatic in many cases, and should be sought for with sensitive methods. How can we distinguish patients with truly primary RP from those who will evolve into CTD (and thus should be screened for CTD and be followed)? The presence of antinuclear antibodies (ANA) and abnormalities at nailfold capillary microscopy (NCM) have proven to be early indicators of evolution into CTD, especially scleroderma and related disorders. The antigenic specificities of ANA indicate which syndrome the patient will develop, e.g., anti-CENP-B indicates the CREST-syndrome and anti-topoisomerase I diffuse scleroderma. Other factors of prognostic significance in patients with RP are age at onset and severity of RP: older age at onset and a highly severe RP represent risk factors for CTD. What do we know about the evolution of RP into CTD? Follow-up studies on patients referred because of RP have shown that some 15-20% of these patients have an insidious progress to limited cutaneous scleroderma including CREST. Risk factors have already been mentioned. From a pathophysiological point of view, studies in patients with early scleroderma have proved that microvascular changes are crucial in the disease process. These changes, demonstrated morphologically by NCM and functionally, e.g., by pulmonary function studies, are also reflected in increased levels of VIII antigen and in in vivo platelet activation. Both of these phenomena probably result from endothelial damage. There is increasing evidence that T-cells and their products are involved in vascular damage in early scleroderma. Future research should be directed to the elucidation of the target antigens for these T-cells.