Inclusion Criteria:

1. Patients must have histologically or cytologically confirmed stage IV or unresectable stage III metastatic melanoma of cutaneous, mucosal or unknown origin.
2. Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as 15 mm or longer with conventional techniques or with spiral CT scan. In case of obviously visible cutaneous metastatic lesions, the margins of the lesions should be clearly defined and measured in at least one dimension as 10 mm or longer. See section 11.0 for the evaluation of measurable disease.
3. Patient may have received prior interferon therapy (only in an adjuvant setting for resected stage III melanoma) and/or up to 1 prior systemic treatment regimen (chemotherapy, biotherapy, or biochemotherapy) for stage IV disease. Active vaccine therapy will not be considered as "prior systemic treatment".
4. Radiographic studies used to assess disease must have been performed within 21 days prior to registration. If a target lesion has been previously embolized, perfused or irradiated, there must be objective evidence of progression before start of therapy to be considered for response assessment.
5. Age of 18 years or older
6. ECOG performance status of 2 or less (or Karnofsky 60% or higher).
7. Patients must have normal organ and marrow function as defined in the protocol.
8. Patient must have a hemoglobin of at least 9 gm/dl (this may be achieved by transfusion if needed) obtained within 14 days prior to registration. In case that PRBC transfusion is needed to obtain a hemoglobin level of at least 9 gm/dl, the hemoglobin level should not be reduced more than 1 gm/dl for at least 1 week.
9. The effects of EMD 121974 on the developing human fetus at the recommended therapeutic dose are unknown. For this reason and because antiangiogenic agents are known to be teratogenic, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately.
10. Ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria:

1. Patients with metastatic melanoma of choroidal origin
2. Patients must not have received the following drugs prior to enrollment: endostatin, angiostatin, bevacizumab or any integrin-targeted drugs
3. Subjects who require concurrent treatment with a non-permitted medication (such as anticoagulant therapy other than for flushing of intravenous port device, or used for thrombosis prophylaxis)
4. Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered to grade 1 toxicity from adverse events due to agents administered more than 4 weeks earlier.
5. Patients may not be receiving any other investigational agents.
6. Patients with known brain metastases should be excluded from this clinical trial. However, the following is an exception; patients who have no radiographical evidence of recurrences in the brain for at least 3 months after the complete resection of the brain metastases or who have asymptomatic brain metastases stable for at least 3 months since the whole brain radiation therapy and/or stereotactic radiosurgery will be eligible for this study. Patients must not require a steroid treatment for brain metastases.
7. Subjects with a history of wound-healing disorders, advanced coronary disease (such as unstable angina pectoris or arrhythmia LOWN IV, cardiac or cardiovascular abnormalities NYHA III/IV), or with a recent history (within 6 months) of peptic ulcer disease.
8. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
9. Pregnant women are excluded from this study because EMD 121974 is an antiangiogenic agent with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with EMD 121974, breastfeeding should be discontinued if the mother is treated with EMD 121974. Lactating women must not breastfeed.
10. No other prior malignancy is allowed except for the following: adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated Stage I or II cancer from which the patient is currently in complete remission, or any other cancer from which the patient has been disease-free for 5 years.